3-sulfonyl-5-aminopyridine-2,4-diol apj agonists

ABSTRACT

The present invention provides compounds of Formula (I) wherein all variables are as defined in the specification, and compositions comprising any of such novel compounds. These compounds are APJ agonists which may be used as medicaments.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is entitled to priority pursuant to 35 U.S.C. § 119(e)to U.S. provisional patent application No. 62/408,272, filed Oct. 14,2016, which is incorporated herein in its entirety.

FIELD OF THE INVENTION

The present invention provides novel 3-sulfonyl-5-aminopyridine-2,4-diolcompounds, and their analogues thereof, which are APJ agonists,compositions containing them, and methods of using them, for example,for the treatment or prophylaxis of heart failure, atherosclerosis,ischemic heart disease and related conditions.

BACKGROUND OF THE INVENTION

Heart failure (HF) and related complications constitute major healthburden in developed countries with an estimated prevalence of 5,700,000in the United States alone (Roger, V. L. et al., Circulation,125(1):e2-e220 (2012)). Despite considerable advances in recent twodecades, the prognosis remains very poor, with survival rates of only˜50% within 5-years of diagnosis (Roger, V. L. et al., JAMA,292(3):344-350 (2004)). In addition to poor survival, the impairedquality of life and recurrent hospitalizations constitute clear unmetmedical need for development of novel treatment options.

HF is a clinical syndrome characterized by the inability of the heart todeliver sufficient supply of blood and oxygen to meet the metabolicdemands of organs in the body. Main symptoms associated with HF includeshortness of breath due to pulmonary edema, fatigue, reduced toleranceto exercise and lower extremity edemas. The etiology of HF is highlycomplex with multiple associated risk factors and potential causes.

Among the leading causes of HF are coronary artery disease and cardiacischemic, acute myocardial infarction, intrinsic cardiomyopathies andchronic uncontrolled hypertension. HF can develop either acutely(functional impairment post myocardial infarction) or as a chroniccondition, characterized by long-term maladaptive cardiac tissueremodeling, hypertrophy and cardiac dysfunction (for example due touncontrolled long-term hypertension). According to the diagnosticcriteria and type of ventricular dysfunction, HF is classified to twomajor groups, HF with “reduced ejection fraction” (HFrEF) or HF with“preserved ejection fraction” (HFpEF). Both types are associated withsimilar signs and symptoms, but differ in the type of ventricularfunctional impairment (Borlaug, B. A. et al., Eur. Heart J.,32(6):670-679 (2011)).

APJ receptor (APLNR) and its endogenous peptidic ligand apelin have beenimplicated as important modulators of cardiovascular function andcandidates for therapeutic intervention in HF (for review see Japp, A.G. et al., Biochem. Pharmacol., 75(10):1882-1892 (2008)).

Accumulated evidence from preclinical disease models and human heartfailure patients have implicated apelin and APJ agonism as beneficial inthe setting of HF. Mice lacking Apelin or APJ gene have impaired myocytecontractility (Charo, D. N. et al., Am. J. Physiol. Heart Circ.Physiol., 297(5):H1904-H1913 (2009)). Apelin knockout (KO) mice developprogressive cardiac dysfunction with aging and are more susceptible toHF in the model of trans-aortic constriction (TAC) (Kuba, K. et al.,Circ. Res., 101(4):e32-42 (2007)). The functional impairment in chronicHF is a result of prolonged demand on the heart and is associated withmaladaptive cardiac remodeling, manifested by the cardiac hypertrophy,increased inflammation and interstitial fibrosis which eventually leadto decrease in cardiac performance.

Acute administration of apelin increases cardiac output in rodents undernormal conditions and also in models of heart failure (Berry, M. F.,Circulation, 110(11 Suppl. 1):H187-H193 (2004)). Increased cardiacoutput is a result of direct augmentation of cardiac contractility andreduced peripheral vascular resistance in the arterial and venous beds(Ashley, E. A., Cardiovasc. Res., 65(1):73-82 (2005)). Reduction in thevascular resistance leads to lower pre-load and after-load on the heartand thus lesser work load (Cheng, X. et al., Eur. J. Pharmacol.,470(3):171-175 (2003)). Similar to rodent studies, acute infusion ofapelin to healthy human subjects and patients with heart failureproduces similar hemodynamic responses with increased cardiac output andincreased vasodilatory response in peripheral and coronary arteries(Japp, A. G. et al., Circulation, 121(16)1818-1827 (2010)).

The mechanisms underlying inotropic action of apelin are not wellunderstood, but appear to be distinct from clinically used β₁-adrenergicagonists (dobutamine) due to lack of increase in heart rate. Thevasodilatory action of apelin is primarily mediated via endothelialnitric oxide synthase pathways (Tatemoto, K., Regul. Pept.,99(2-3):87-92 (2001)). Apelin is induced under hypoxic conditions,promotes angiogenesis and has been shown to limit the infarct size inischemia-reperfusion models (Simpkin, J. C., Basic Res. Cardiol.,102(6):518-528 (2007)).

In addition to aforementioned studies evaluating acute administration ofapelin, several studies have clearly demonstrated beneficial effects ofprolonged administration of apelin in a number of chronic rodent modelsof HF, including the angiotensin II model, TAC model and rat Dahlsalt-sensitive model (Siddiquee, K. et al., J. Hypertens., 29(4):724-731(2011); Scimia, M. C. et al., Nature, 488(7411):394-398 (2012); Koguchi,W. et al., Circ. J., 76(1):137-144 (2012)). In these studies, prolongedapelin infusion reduced cardiac hypertrophy and cardiac fibrosis, andwas associated with improvement in cardiac performance.

Genetic evidence is also emerging that polymorphisms in the APJ gene areassociated with slower progression of HF (Sarzani, R. et al., J. Card.Fail., 13(7):521-529 (2007)). Importantly, while expression of APJ andapelin can be reduced or vary considerably with HF progression, thecardiovascular hemodynamic effects of apelin are sustained in patientswith developed HF and receiving standard of care therapy (Japp, A. G. etal., Circulation, 121(16):1818-1827 (2010)).

In summary, there is a significant amount of evidence to indicate thatAPJ receptor agonism plays a cardioprotective role in HF and would be ofpotential benefit to HF patients. Apelin's very short half life incirculation limits its therapeutic utility, and consequently, there is aneed for APJ receptor agonists with improved pharmacokinetic andsignaling profile while maintaining or enhancing the beneficial effectsof endogenous APJ agonist apelin.

SUMMARY OF THE INVENTION

The present invention provides 3-sulfonyl-5-aminopyridine-2,4-diolcompounds, and their analogues thereof, which are useful as APJagonists, including stereoisomers, tautomers, pharmaceuticallyacceptable salts, or solvates thereof.

The present invention also provides processes and intermediates formaking the compounds of the present invention or stereoisomers,tautomers, pharmaceutically acceptable salts, or solvates thereof.

The present invention also provides pharmaceutical compositionscomprising a pharmaceutically acceptable carrier and at least one of thecompounds of the present invention or stereoisomers, tautomers,pharmaceutically acceptable salts, or solvates thereof.

The compounds of the invention may be used in the treatment and/orprophylaxis of multiple diseases or disorders associated with APJ, suchas heart failure, coronary artery disease, cardiomyopathy, diabetes andrelated conditions including but not limited to acute coronary syndrome,myocardial ischemia, hypertension, pulmonary hypertension, coronaryvasospasm, cerebral vasospasm, ischemia/reperfusion injury, angina,renal disease, metabolic syndrome and insulin resistance.

The compounds of the invention may be used in therapy.

The compounds of the invention may be used for the manufacture of amedicament for the treatment and/or prophylaxis of multiple diseases ordisorders associated with APJ.

The compounds of the invention can be used alone, in combination withother compounds of the present invention, or in combination with one ormore other agent(s).

Other features and advantages of the invention will be apparent from thefollowing detailed description and claims.

DETAILED DESCRIPTION OF THE INVENTION I. COMPOUNDS OF THE INVENTION

In a first aspect, the present invention provides, inter alia, compoundsof Formula (I):

-   or stereoisomers, enantiomers, diastereomers, tautomers,    pharmaceutically acceptable salts, solvates, or prodrugs thereof,    wherein-   R¹ is independently selected from

-   Ring A is independently selected from

-   Ring B is independently selected from aryl and heterocyclyl    comprising carbon atoms and 1-4 heteroatoms selected from N,    NR^(3a), O, and S, each substituted with 1-3 R³ and 1-2 R⁵; provided    R³ and R⁵ are not both H;-   R² is independently selected from C₁₋₅ alkyl substituted with 0-3    R^(e); C₂₋₅ alkenyl substituted with 0-3 R^(e), aryl substituted    with 0-3 R^(e), heterocyclyl substituted with 0-3 R^(e), and C₃₋₆    cycloalkyl substituted with 0-3 R^(e); provided when R² is C₁₋₅    alkyl, the carbon atom except the one attached to the pyridine ring    may be replaced by O, N, and S;-   R³ is independently selected from H, F, Cl, Br, C₁₋₅ alkyl    substituted with 0-3 R^(e), C₂₋₅ alkenyl substituted with 0-3 R^(e),    —(CH₂)_(n)OR^(b), —(CH₂)_(n)NR^(a)R^(a), —(CH₂)_(n)CN,    —(CH₂)_(n)C(═O)R^(b), —(CH₂)_(n)C(═O)OR^(b),    —(CH₂)_(n)C(═O)NR^(a)R^(a), —(CH₂)_(n)NHC(═O)R^(b),    —(CH₂)_(n)NHC(═O)NR^(a)R^(a), —(CH₂)_(n)NHC(═O)OR^(b),    —(CH₂)_(n)NHS(O)_(p)NR^(a)R^(a),    —(CH₂)_(n)NHS(O)_(p)R^(c)—(CH₂)_(n)S(O)_(p)R_(c),    —(CH₂)_(n)S(O)_(p)NR^(a)R^(a), —(CH₂)_(n)OC(═O)NR^(a)R^(a);-   R^(3a) is independently selected from H, C₁₋₅ alkyl substituted with    0-3 R^(e), —S(O)_(p)R_(c), —C(═O)R^(b), —C(═O)NR^(a)R^(a),    —C(═O)OR^(b), —S(O)_(p)NR^(a)R^(a), R⁶, —S(O)_(p)R⁶, —C(═O)R⁶,    —C(═O)NR^(a)R⁶, —C(═O)OR⁶, and —S(O)_(p)NR^(a)R⁶;-   R⁴ is independently selected from H, C₁₋₅ alkyl substituted with 0-3    R^(e), C₂₋₅ alkenyl substituted with 0-3 R^(e), —(CH₂)_(n)—C₃₋₆    carbocyclyl substituted with 0-3 R^(e), and —(CH₂)_(n)-heterocyclyl    substituted with 0-3 R^(e);-   R⁵ is independently selected from H, R⁶, —OR⁶, —S(O)_(p)R⁶,    —C(═O)R⁶, —C(═O)OR⁶, —NR^(a)R⁶, —C(═O)NR^(a)R⁶, —NR^(a)C(═O)R⁶,    —NR^(a)C(═O)OR⁶, —OC(═O)NR^(a)R⁶, —S(O)_(p)NR^(a)R⁶,    —NR^(a)S(O)_(p)NR^(a)R⁶, and —NR^(a)S(O)_(p)R⁶;-   R⁶ independently selected from —(CR⁷R⁷)_(n)-aryl, —(CR⁷R⁷)_(n)—C₃₋₆    cycloalkyl, and —(CR⁷R⁷)_(n)-heteroaryl, each substituted with 1-6    R⁸;-   R⁷ is independently selected from H, C₁₋₄ alkyl, and    —(CH₂)_(n)—C₃₋₁₂ carbocyclyl substituted with 0-3 R^(e);-   R⁸ is independently selected from H, F, Cl, Br, —(CH₂)_(n)CN,    —(CH₂)_(n)OR^(b), —(CH₂)_(n)C(═O)R^(b), —(CH₂)_(n)C(═O)OR^(b),    —(CH₂)_(n)C(═O)NR^(a)R^(a), —(CH₂)_(n)NR^(a)R^(a),    —(CH₂)_(n)NR^(a)C(═O)R^(b), —(CH₂)_(n)NR^(a)C(═O)OR^(b),    —(CH₂)_(n)NR^(a)C(═O)NR^(a)R^(a), —(CH₂)_(n)OC(═O)NR^(a)R^(a),    —(CH₂)_(n)S(O)_(p)R_(c), —(CH₂)_(n)S(O)_(p)NR^(a)R^(a),    —(CH₂)_(n)NR^(a)S(O)_(p)NR^(a)R^(a), —(CH₂)_(n)NR^(a)S(O)_(p)R^(c),    C₁₋₄ alkyl substituted with 0-3 R^(e), —(CH₂)_(n)—C₃₋₆ carbocyclyl    substituted with 0-3 R^(e), and —(CH₂)_(n)-heterocyclyl substituted    with 0-3 R^(e);-   R⁹ is independently selected from C₃₋₆ cycloalkyl, C₃₋₆    cycloalkenyl, aryl, bicyclic carbocyclyl, 6-membered heteroaryl,    bicyclic heterocyclyl, each substituted with 1-6 R¹⁰;-   alternatively, R⁴ and R⁹ together with the nitrogen atom to which    they are both attached form a mono or bicyclic heterocyclic ring    substituted with 1-6 R¹⁰;-   R¹⁰ is independently selected from H, F, Cl, Br, NO₂,    —(CH₂)_(n)OR^(b), —(CH₂)_(n)S(O)_(p)R_(c), —(CH₂)_(n)C(═O)R^(b),    —(CH₂)_(n)NR^(a)R^(a), —(CH₂)_(n)CN, —(CH₂)_(n)C(═O)NR^(a)R^(a),    —(CH₂)_(n)NR^(a)C(═O)R^(b), —(CH₂)_(n)NR^(a)C(═O)NR^(a)R^(a),    —(CH₂)_(n)NR^(a)C(═O)OR^(b), —(CH₂)_(n)OC(═O)NR^(a)R^(a),    —(CH₂)_(n)C(═O)OR^(b), —(CH₂)_(n)S(O)_(p)NR^(a)R^(a),    —(CH₂)_(n)NR^(a)S(O)_(p)NR^(a)R^(a), —(CH₂)_(n)NR^(a)S(O)_(p)R^(c),    C₁₋₄ alkyl substituted with 0-3 R^(e), —(CH₂)_(n)—C₃₋₆ carbocyclyl    substituted with 0-3 R^(e), and —(CH₂)_(n)-heterocyclyl substituted    with 0-3 R^(e);-   R^(a) is independently selected from H, C₁₋₆ alkyl substituted with    0-5 R^(e), C₂₋₆ alkenyl substituted with 0-5 R^(e), C₂₋₆ alkynyl    substituted with 0-5 R^(e), —(CH₂)_(n)—C₃₋₁₀carbocyclyl substituted    with 0-5 R^(e), and —(CH₂)_(n)-heterocyclyl substituted with 0-5    R^(e); or R^(a) and R^(a) together with the nitrogen atom to which    they are both attached form a heterocyclic ring substituted with 0-5    R^(e);-   R^(b) is independently selected from H, C₁₋₆ alkyl substituted with    0-5 R^(e), C₂₋₆ alkenyl substituted with 0-5 R^(e), C₂₋₆ alkynyl    substituted with 0-5 R^(e), —(CH₂)_(n)—C₃₋₁₀carbocyclyl substituted    with 0-5 R^(e), and —(CH₂)_(n)-heterocyclyl substituted with 0-5    R^(e);-   R^(c) is independently selected from C₁₋₆ alkyl substituted with 0-5    R^(c), C₂₋₆alkenyl substituted with 0-5 R^(e), C₂₋₆alkynyl    substituted with 0-5 R^(e), C₃₋₆carbocyclyl, and heterocyclyl;-   R^(d) is independently selected from H and C₁₋₄alkyl substituted    with 0-5 R^(e);-   R^(e) is independently selected from C₁₋₆ alkyl substituted with 0-5    R^(f), C₂₋₆ alkenyl, C₂₋₆ alkynyl, —(CH₂)_(n)—C₃₋₆ cycloalkyl,    —(CH₂)_(n)—C₄₋₆ heterocyclyl, —(CH₂)_(n)-aryl,    —(CH₂)_(n)-heteroaryl, F, Cl, Br, CN, NO₂, ═O, CO₂H,    —(CH₂)_(n)OR^(f), S(O)_(p)R^(f), C(═O)NR^(f)R^(f), NR^(f)C(═O)R^(f),    S(O)_(p)NR^(f)R^(f), NR^(f)S(O)_(p)R^(f), NR^(f)C(═O)OR^(f),    OC(═O)NR^(f)R^(f) and —(CH₂)_(n)NR^(f)R^(f);-   R^(f) is independently selected from H, F, Cl, Br, CN, OH, C₁₋₅alkyl    (optimally substituted with F, Cl, Br and OH), C₃₋₆ cycloalkyl, and    phenyl, or R^(f) and R^(f) together with the nitrogen atom to which    they are both attached form a heterocyclic ring optionally    substituted with C₁₋₄alkyl;-   n is independently selected from zero, 1, 3, and 4; and-   p is independently selected from zero, 1, and 2.

In a second aspect, the present invention provides compounds of Formula(II):

-   or stereoisomers, enantiomers, diastereomers, tautomers,    pharmaceutically acceptable salts, solvates, or prodrugs thereof,    within the scope of the first aspect, wherein-   Ring B is independently selected from

-   R² is independently selected from C₁₋₅ alkyl substituted with 0-3    R^(e); C₂₋₅ alkenyl, aryl substituted with 0-3 R^(e), heterocyclyl    substituted with 0-3 R^(e), and C₃₋₆ cycloalkyl; provided when R² is    C₁₋₅ alkyl, the carbon atom except the one attached to the pyridine    ring may be replaced by O, N, and S;-   R³ is independently selected from H, F, Cl, Br, C₁₋₅ alkyl    substituted with 0-3 R^(e), C₂₋₄ alkenyl; —OR^(b), —NR^(a)R^(a),    —CN, —C(═O)R^(b), —C(═O)OR^(b), —C(═O)NR^(a)R^(a), —NHC(═O)R^(b),    —NHC(═O)NR^(a)R^(a), —NHC(═O)OR^(b), —NHS(O)_(p)R^(c)—S(O)_(p)R_(c),    —S(O)_(p)NR^(a)R^(a), —OC(═O)NR^(a)R^(a);-   R^(3a) is independently selected from H, C₁₋₅ alkyl substituted with    0-3 R^(e), —C(═O)R^(b), —C(═O)NR^(a)R^(a), —C(═O)OR^(b), R⁶,    —S(O)_(p)R⁶, —C(═O)R⁶, —C(═O)NR^(a)R⁶, —C(═O)OR⁶, and    —S(O)_(p)NR^(a)R⁶;-   R⁴ is independently selected from H and C₁₋₅ alkyl substituted with    0-3 R^(e);-   R⁵ is independently selected from H, R⁶, —OR⁶, —S(O)_(p)R⁶,    —C(═O)R⁶, —C(═O)OR⁶, —NR^(a)R⁶, —C(═O)NR^(a)R⁶, —NR^(a)C(═O)R⁶,    —NR^(a)C(═O)OR⁶, —OC(═O)NR^(a)R⁶, —S(O)_(p)NR^(a)R⁶,    —NR^(a)S(O)_(p)NR^(a)R⁶, and —NR^(a)S(O)_(p)R⁶;-   R⁶ is independently selected from —(CR⁷R⁷)_(n)-aryl,    —(CR⁷R⁷)_(n)—C₃₋₆ cycloalkyl, and —(CR⁷R⁷)_(n)-heteroaryl, each    substituted with 1-4 R⁸;-   R⁷ is independently selected from H and C₁₋₄ alkyl;-   R⁸ is independently selected from H, F, Cl, Br, —(CH₂)_(n)OR^(b),    —(CH₂)_(n)C(═O)R^(b), —(CH₂)_(n)C(═O)OR^(b), —(CH₂)_(n)NR^(a)R^(a),    CN, —(CH₂)_(n)C(═O)NR^(a)R^(a), —NHC(═O)OR^(b), C₁₋₄ alkyl    substituted with 0-3 R^(e), (CH₂)_(n)C₃₋₆ carbocyclyl substituted    with 0-3 R^(e), and —(CH₂)_(n)-heterocyclyl substituted with 0-3    R^(e);-   R⁹ is independently selected from C₃₋₆ cycloalkyl, C₃₋₆    cycloalkenyl, and aryl, each substituted with 1-6 R¹⁰;-   alternatively, R⁴ and R⁹ together with the nitrogen atom to which    they are both attached form a heterocyclic ring selected from

-   R¹⁰ is independently selected from H, F, Cl, Br, —OR^(b), CN, C₁₋₄    alkyl substituted with 0-3 R^(e) and C₃₋₆ cycloalkyl substituted    with 0-3 R^(e);-   R^(a) is independently selected from H, C₁₋₆ alkyl substituted with    0-5 R^(e), —(CH₂)_(n)—C₃₋₁₀carbocyclyl substituted with 0-5 R^(e),    and —(CH₂)_(n)-heterocyclyl substituted with 0-5 R^(e); or R^(a) and    R^(a) together with the nitrogen atom to which they are both    attached form a heterocyclic ring substituted with 0-5 R^(e);-   R^(b) is independently selected from H, C₁₋₆ alkyl substituted with    0-5 R^(e), C₂₋₆ alkenyl substituted with 0-5 R^(e), C₂₋₆ alkynyl    substituted with 0-5 R^(e), —(CH₂)_(n)—C₃₋₁₀carbocyclyl substituted    with 0-5 R^(e), and —(CH₂)_(n)-heterocyclyl substituted with 0-5    R^(e);-   R^(e) is independently selected from C₁₋₆ alkyl substituted with 0-5    R^(f), C₂₋₆ alkenyl, C₂₋₆ alkynyl, —(CH₂)_(n)—C₃₋₆ cycloalkyl,    —(CH₂)_(n)—C₄₋₆ heterocyclyl, —(CH₂)_(n)-aryl,    —(CH₂)_(n)-heteroaryl, F, Cl, Br, CN, NO₂, ═O, CO₂H,    —(CH₂)_(n)OR^(f), S(O)_(p)R^(f), C(═O)NR^(f)R^(f), NR^(f)C(═O)R^(f),    S(O)_(p)NR^(f)R^(f), NR^(f)S(O)_(p)R^(f), NR^(f)C(═O)OR^(f),    OC(═O)NR^(f)R^(f) and —(CH₂)_(n)NR^(f)R^(f);-   R^(f) is independently selected from H, F, Cl, Br, CN, OH, C₁₋₅alkyl    (optimally substituted with F, Cl, Br and OH), C₃₋₆ cycloalkyl, and    phenyl;-   n is independently selected from zero, 1, 2, and 3; and-   p is independently selected from zero, 1, and 2.

In a third aspect, the present invention provides compounds of Formula(III):

-   or stereoisomers, enantiomers, diastereomers, tautomers,    pharmaceutically acceptable salts, solvates, or prodrugs thereof,    within the scope of the first or second aspect, wherein-   R² is independently selected from C₁₋₅ alkyl substituted with 0-3    R^(e); C₂₋₅ alkenyl, aryl substituted with 0-3 R^(e), 5-6 membered    heterocyclyl substituted with 0-3 R^(e), C₃₋₆ cycloalkyl,    —(CH₂)₁₋₄OC₁₋₅alkyl, and —(CH₂)₁₋₃OC₃₋₆cycloalkyl;-   R³ is independently selected from H, F, Cl, and Br;-   R⁴ is independently selected from H and C₁₋₅ alkyl substituted with    0-3 R^(e);-   R⁵ is independently selected from H, R⁶, —C(═O)R⁶, —NR^(a)R⁶,    —C(═O)NR^(a)R⁶, and —NHC(═O)R⁶;-   R⁶ is independently selected from carbocyclyl selected from

and heterocyclyl selected from

-   R⁸ is independently selected from H, F, Cl, Br, —(CH₂)_(n)OR^(b),    —C(═O)R^(b), —C(═O)OR^(b), —NR^(a)R^(a), CN, —C(═O)NR^(a)R^(a),    —NHC(═O)OR^(b), C₁₋₄ alkyl substituted with 0-3 R^(e),    —(CH₂)_(n)—C₃₋₆ carbocyclyl substituted with 0-3 R^(e), and    —(CH₂)_(n)-heterocyclyl substituted with 0-3 R^(e);-   R⁹ is independently selected from

-   alternatively, R⁴ and R⁹ together with the nitrogen to which they    are both attached form a heterocyclic ring selected from

-   R¹⁰ is independently selected from H, F, Cl, CN, C₁₋₄ alkyl, and    OC₁₋₄ alkyl;-   R^(a) is independently selected from H, C₁₋₆ alkyl substituted with    0-5 R^(e), —(CH₂)_(n)—C₃₋₁₀carbocyclyl substituted with 0-5 R^(e),    and —(CH₂)_(n)-heterocyclyl substituted with 0-5 R^(e); or R^(a) and    R^(a) together with the nitrogen atom to which they are both    attached form a heterocyclic ring substituted with 0-5 R^(e);-   R^(b) is independently selected from H, C₁₋₆ alkyl substituted with    0-5 R^(e), C₂₋₆ alkenyl substituted with 0-5 R^(e), C₂₋₆ alkynyl    substituted with 0-5 R^(e), —(CH₂)_(n)—C₃₋₁₀carbocyclyl substituted    with 0-5 R^(e), and —(CH₂)_(n)-heterocyclyl substituted with 0-5    R^(e);-   R^(e) is independently selected from C₁₋₆ alkyl substituted with 0-5    R^(f), C₂₋₆ alkenyl C₂₋₆ alkynyl, —(CH₂)_(n)—C₃₋₆ cycloalkyl,    —(CH₂)_(n)—C₄₋₆ heterocyclyl, —(CH₂)_(n)-aryl,    —(CH₂)_(n)-heteroaryl, F, Cl, Br, CN, NO₂, ═O, CO₂H,    —(CH₂)_(n)OR^(f), S(O)_(p)R^(f), C(═O)NR^(f)R^(f), NR^(f)C(═O)R^(f),    S(O)_(p)NR^(f)R^(f), NR^(f)S(O)_(p)R^(f), NR^(f)C(═O)OR^(f),    OC(═O)NR^(f)R^(f) and —(CH₂)_(n)NR^(f)R^(f);-   R^(f) is independently selected from H, F, Cl, Br, CN, OH, C₁₋₅alkyl    (optimally substituted with F, Cl, Br and OH), C₃₋₆ cycloalkyl, and    phenyl;-   n is independently selected from zero, 1, 2, and 3; and-   p is independently selected from zero, 1, and 2.

In a fourth aspect, the present invention provides compounds of Formula(IV):

-   or stereoisomers, enantiomers, diastereomers, tautomers,    pharmaceutically acceptable salts, solvates, or prodrugs thereof,    within the scope of any of the first, second and third aspects,    wherein-   R² is independently selected from —CH₂CH₂CH₃, —CH₂CH₂CH₂CH₃,    —CH₂CH₂CH(CH₃)₂,

—CH₂OCH₃, —CH₂OCH₂CH₃, and —CH₂OCH(CH₃)₂;

-   R³ is independently selected from H, F, Cl, and Br;-   R⁴ is independently selected from —CH₃, —CH₂CH₃, —CH₂CH₂CH₃, and    —CH₂(CH₃)₂;-   R⁵ is R⁶;-   R⁶ is independently selected from

-   R⁸ is independently selected from H, F, Cl, Br, —(CH₂)₀₋₁OC₁₋₄    alkyl, C₁₋₄ alkyl and —C(═O)N(C₁₋₄alkyl)₂; and-   R¹⁰ is independently selected from H, F, Cl, CN, —CH₃, —CH₂CH₃, and    —OMe.

In a fifth aspect, the present invention provides compounds of Formula(V):

-   or stereoisomers, enantiomers, diastereomers, tautomers,    pharmaceutically acceptable salts, solvates, or prodrugs thereof,    within the scope of any of the first, second and third aspects,    wherein-   R² is independently selected from —CH₂CH₂CH₃, —CH₂CH₂CH₂CH₃,    —CH₂CH₂CH(CH₃)₂,

—CH₂OCH₃, —CH₂OCH₂CH₃, and —CH₂OCH(CH₃)₂;

-   R³ is independently selected from H, F, Cl, and Br;-   R⁴ and R⁹ together with the nitrogen atom to which they are both    attached form a heterocyclic ring selected from

-   R⁵ is R⁶;-   R⁶ is independently selected from

-   R⁸ is independently selected from H, F, Cl, Br, —(CH₂)₀₋₁OC₁₋₄    alkyl, C₁₋₄ alkyl and —C(═O)N(C₁₋₄alkyl)₂; and-   R¹⁰ is independently selected from H, F, Cl, CN, —CH₃, —CH₂CH₃, and    —OCH₃.

In a sixth aspect, the present invention provides compounds of Formula(VI):

-   or stereoisomers, enantiomers, diastereomers, tautomers,    pharmaceutically acceptable salts, solvates, or prodrugs thereof,    within the scope of the first aspect, wherein-   Ring A is independently selected from    ,

-   R² is independently selected from C₁₋₅ alkyl substituted with 0-3    R^(e); C₂₋₅ alkenyl, aryl substituted with 0-3 R^(e), heterocyclyl    substituted with 0-3 R^(e), and C₃₋₆ cycloalkyl; provided when R² is    C₁₋₅ alkyl, the carbon atom except the one attached to the pyridine    ring may be replaced by O, N, and S;-   R^(3a) is independently selected from H, C₁₋₅ alkyl substituted with    0-3 R^(e), —C(═O)R^(b), —C(═O)NR^(a)R^(a), —C(═O)OR^(b), R⁶,    —S(O)_(p)R⁶, —C(═O)R⁶, —C(═O)NR^(a)R⁶, —C(═O)OR⁶, and    —S(O)_(p)NR^(a)R⁶;-   R⁴ is independently selected from H and C₁₋₅ alkyl substituted with    0-3 R^(e);-   R⁵ is independently selected from H, R⁶, —OR⁶, —S(O)_(p)R⁶,    —C(═O)R⁶, —C(═O)OR⁶, —NR^(a)R⁶, —C(═O)NR^(a)R⁶, —NR^(a)C(═O)R⁶,    —NR^(a)C(═O)OR⁶, —OC(═O)NR^(a)R⁶, —S(O)_(p)NR^(a)R⁶,    —NR^(a)S(O)_(p)NR^(a)R⁶, and —NR^(a)S(O)_(p)R⁶;-   R⁶ is independently selected from —(CR⁷R⁷)_(n)-aryl,    —(CR⁷R⁷)_(n)—C₃₋₆ cycloalkyl, and —(CR⁷R⁷)_(n)-heteroaryl, each    substituted with 1-4 R⁸;-   R⁷ is independently selected from H and C₁₋₄ alkyl;-   R⁸ is independently selected from H, F, Cl, Br, —OR^(b),    —(CH₂)_(n)C(═O)R^(b), —(CH₂)_(n)C(═O)OR^(b), —(CH₂)_(n)NR^(a)R^(a),    CN, —(CH₂)_(n)C(═O)NR^(a)R^(a), —NHC(═O)OR^(b), C₁₋₄ alkyl    substituted with 0-3 R^(e), —(CH₂)_(n)—C₃₋₆ carbocyclyl substituted    with 0-3 R^(e), and —(CH₂)_(n)-heterocyclyl substituted with 0-3    R^(e);-   R⁹ is independently selected from C₃₋₆ cycloalkyl, C₃₋₆    cycloalkenyl, and aryl, each substituted with 1-3 R¹⁰;-   alternatively, R⁴ and R⁹ together with the nitrogen atom to which    they are both attached form a heterocyclic ring selected from

-   R¹⁰ is independently selected from H, F, Cl, Br, —OR^(b), CN, C₁₋₄    alkyl substituted with 0-3 R^(e) and C₃₋₆ cycloalkyl substituted    with 0-3 R^(e);-   R^(a) is independently selected from H, C₁₋₆ alkyl substituted with    0-5 R^(e), —(CH₂)_(n)—C₃₋₁₀carbocyclyl substituted with 0-5 R^(e),    and —(CH₂)_(n)-heterocyclyl substituted with 0-5 R^(e); or R^(a) and    R^(a) together with the nitrogen atom to which they are both    attached form a heterocyclic ring substituted with 0-5 R^(e);-   R^(b) is independently selected from H, C₁₋₆ alkyl substituted with    0-5 R^(e), C₂₋₆ alkenyl substituted with 0-5 R^(e), C₂₋₆ alkynyl    substituted with 0-5 R^(e), —(CH₂)_(n)—C₃₋₁₀carbocyclyl substituted    with 0-5 R^(e), and —(CH₂)_(n)-heterocyclyl substituted with 0-5    R^(e);-   R^(e) is independently selected from C₁₋₆ alkyl substituted with 0-5    R^(f), C₂₋₆ alkenyl, C₂₋₆ alkynyl, —(CH₂)_(n)—C₃₋₆ cycloalkyl,    —(CH₂)_(n)—C₄₋₆ heterocyclyl, —(CH₂)_(n)-aryl,    —(CH₂)_(n)-heteroaryl, F, Cl, Br, CN, NO₂, ═O, CO₂H,    —(CH₂)_(n)OR^(f), S(O)_(p)R^(f), C(═O)NR^(f)R^(f), NR^(f)C(═O)R^(f),    S(O)_(p)NR^(f)R^(f), NR^(f)S(O)_(p)R^(f), NR^(f)C(═O)OR^(f),    OC(═O)NR^(f)R^(f) and —(CH₂)_(n)NR^(f)R^(f);-   R^(f) is independently selected from H, F, Cl, Br, CN, OH, C₁₋₅alkyl    (optimally substituted with F, Cl, Br and OH), C₃₋₆ cycloalkyl, and    phenyl;-   n is independently selected from zero, 1, 2, and 3; and-   p is independently selected from zero, 1, and 2.

In a seventh aspect, the present invention provides compounds of Formula(VI), or stereoisomers, enantiomers, diastereomers, tautomers,pharmaceutically acceptable salts, solvates, or prodrugs thereof, withinthe scope of the first and sixth aspects, wherein

-   Ring A is independently selected from

-   R² is independently selected from C₁₋₅ alkyl substituted with 0-3    R^(e); C₂₋₅ alkenyl, aryl substituted with 0-3 R^(e), 5-6 membered    heterocyclyl substituted with 0-3 R^(e), C₃₋₆ cycloalkyl,    —(CH₂)₁₋₄OC₁₋₅alkyl, and —(CH₂)₁₋₃OC₃₋₆cycloalkyl;-   R^(3a) is independently selected from H and C₁₋₅ alkyl substituted    with 0-3 R^(e);-   R⁴ is independently selected from H and C₁₋₅ alkyl substituted with    0-3 R^(e);-   R⁵ is independently selected H and R⁶;-   R⁶ is independently selected from carbocyclyl selected from

and heterocyclyl selected from

-   R⁸ is independently selected from H, F, Cl, Br, —OR^(b),    —C(═O)R^(b), —C(═O)OR^(b), —NR^(a)R^(a), CN, —C(═O)NR^(a)R^(a),    —NHC(═O)OR^(b), C₁₋₄ alkyl substituted with 0-3 R^(e),    —(CH₂)_(n)—C₃₋₆ carbocyclyl substituted with 0-3 R^(e), and    —(CH₂)_(n)-heterocyclyl substituted with 0-3 R^(e);-   R⁹ is independently selected from

-   alternatively, R⁴ and R⁹ together with the nitrogen to which they    are both attached form a heterocyclic ring selected from

-   R¹⁰ is independently selected from H, F, Cl, CN, C₁₋₄ alkyl, and    OC₁₋₄ alkyl;-   R^(a) is independently selected from H, C₁₋₆ alkyl substituted with    0-5 R^(e), —(CH₂)_(n)—C₃₋₁₀carbocyclyl substituted with 0-5 R^(e),    and —(CH₂)_(n)-heterocyclyl substituted with 0-5 R^(e); or R^(a) and    R^(a) together with the nitrogen atom to which they are both    attached form a heterocyclic ring substituted with 0-5 R^(e);-   R^(b) is independently selected from H, C₁₋₆ alkyl substituted with    0-5 R^(e), C₂₋₆ alkenyl substituted with 0-5 R^(e), C₂₋₆ alkynyl    substituted with 0-5 R^(e), —(CH₂)_(n)—C₃₋₁₀carbocyclyl substituted    with 0-5 R^(e), and —(CH₂)_(n)-heterocyclyl substituted with 0-5    R^(e);-   R^(e) is independently selected from C₁₋₆ alkyl substituted with 0-5    R^(f), C₂₋₆ alkenyl, C₂₋₆ alkenyl, —(CH₂)_(n)—C₃₋₆ cycloalkyl,    —(CH₂)_(n)—C₄₋₆ heterocyclyl, —(CH₂)_(n)-aryl,    —(CH₂)_(n)-heteroaryl, F, Cl, Br, CN, NO₂, ═O, CO₂H,    —(CH₂)_(n)OR^(f), S(O)_(p)R^(f), C(═O)NR^(f)R^(f), NR^(f)C(═O)R^(f),    S(O)_(p)NR^(f)R^(f), NR^(f)S(O)_(p)R^(f), NR^(f)C(═O)O R^(f),    OC(═O)NR^(f)R^(f) and —(CH₂)_(n)NR^(f)R^(f);-   R^(f) is independently selected from H, F, Cl, Br, CN, OH, C₁₋₅alkyl    (optimally substituted with F, Cl, Br and OH), C₃₋₆ cycloalkyl, and    phenyl;-   n is independently selected from zero, 1, 2, and 3; and-   p is independently selected from zero, 1, and 2.

In an eighth aspect, the present invention provides compounds of Formula(VII):

-   or stereoisomers, enantiomers, diastereomers, tautomers,    pharmaceutically acceptable salts, solvates, or prodrugs thereof,    within the scope of the first, sixth, and seventh aspects, wherein-   R² is independently selected from C₁₋₅ alkyl substituted with 0-3    R^(e); C₂₋₅ alkenyl, aryl substituted with 0-3 R^(e), 5-6 membered    heterocyclyl substituted with 0-3 R^(e), C₃₋₆ cycloalkyl,    —(CH₂)₁₋₄OC₁₋₅alkyl, and —(CH₂)₁₋₃OC₃₋₆cycloalkyl;-   R⁴ is independently selected from H and C₁₋₄ alkyl;-   R⁵ is independently selected from H and R⁶;-   R⁶ is independently selected from

-   R⁸ is independently selected from H, F, Cl, Br, —(CH₂)₀₋₁OC₁₋₄    alkyl, C₁₋₄ alkyl, and —C(═O)N(C₁₋₄alkyl)₂;-   R⁹ is independently selected from

-   alternatively, R⁴ and R⁹ together with the nitrogen atom to which    they are both attached form a heterocyclic ring selected from

-   R¹⁰ is independently selected from H, F, Cl, CN, C₁₋₄ alkyl, and    OC₁₋₄ alkyl;-   R^(a) is independently selected from H, C₁₋₆ alkyl substituted with    0-5 R^(e), —(CH₂)_(n)—C₃₋₁₀carbocyclyl substituted with 0-5 R^(e),    and —(CH₂)_(n)-heterocyclyl substituted with 0-5 R^(e); or R^(a) and    R^(a) together with the nitrogen atom to which they are both    attached form a heterocyclic ring substituted with 0-5 R^(e);-   R^(b) is independently selected from H, C₁₋₆ alkyl substituted with    0-5 R^(e), C₃₋₁₀carbocyclyl, and heterocyclyl substituted with 0-5    R^(e);-   R^(e) is independently selected from C₁₋₆ alkyl (optionally    substituted with F and Cl), OH, OCH₃, OCF₃, —(CH₂)_(n)—C₃₋₆    cycloalkyl, —(CH₂)_(n)—C₄₋₆ heterocyclyl, —(CH₂)_(n)-aryl,    —(CH₂)_(n)-heteroaryl, F, Cl, Br, CN, NO₂, ═O, and CO₂H; and-   n is independently selected from zero, 1, 2, and 3.

In a ninth aspect, the present invention provides compounds of Formula(VII), or stereoisomers, enantiomers, diastereomers, tautomers,pharmaceutically acceptable salts, solvates, or prodrugs thereof, withinthe scope of the first, sixth, seventh, and eighth aspects, wherein

-   R² is independently selected from —CH₂CH₂CH₃, —CH₂CH₂CH₂CH₃,    —CH₂CH₂CH(CH₃)₂,

—CH₂OCH₃, —CH₂OCH₂CH₃, and —CH₂OCH(CH₃)₂;

-   R⁴ is independently selected from —CH₃, —CH₂CH₃, —CH₂CH₂CH₃, and    —CH₂(CH₃)₂;-   R⁵ is R⁶;-   R⁶ is independently selected from

-   R⁸ is independently selected from H, F, Cl, and Br;-   R⁹ is

-   alternatively, R⁴ and R⁹ together with the nitrogen atom to which    they are both attached form a heterocyclic ring selected from

and

-   R¹⁰ is independently selected from H, F, Cl, CN, C₁₋₄ alkyl, and    OC₁₋₄ alkyl.

In a tenth aspect, the present invention provides compounds of Formula(VII), or stereoisomers, enantiomers, diastereomers, tautomers,pharmaceutically acceptable salts, solvates, or prodrugs thereof, withinthe scope of the first, sixth, seventh, eighth, and ninth aspects,wherein

-   R⁹ is

and

-   R¹⁰ is independently selected from H, F, Cl, CN, C₁₋₄ alkyl, and    OC₁₋₄ alkyl.

In an eleventh aspect, the present invention provides compounds ofFormula (VII), or stereoisomers, enantiomers, diastereomers, tautomers,pharmaceutically acceptable salts, solvates, or prodrugs thereof, withinthe scope of the first, sixth, seventh, eighth, and ninth aspects,wherein

-   R⁴ and R⁹ together with the nitrogen atom to which they are both    attached form a heterocyclic ring selected from

and

-   R¹⁰ is independently selected from H, F, Cl, CN, C₁₋₄ alkyl, and    OC₁₋₄ alkyl.

The invention may be embodied in other specific forms without departingfrom the spirit or essential attributes thereof. This invention alsoencompasses all combinations of alternative aspects of the inventionnoted herein. It is understood that any and all embodiments of thepresent invention may be taken in conjunction with any other embodimentto describe additional embodiments of the present invention.Furthermore, any elements (including individual variable definitions) ofan embodiment are meant to be combined with any and all other elementsfrom any of the embodiments to describe additional embodiments. Thepresent invention also provides a pharmaceutical composition comprisinga compound of formula I, or an enantiomer, diastereomer, or apharmaceutically-acceptable salt, and a pharmaceutically acceptablecarrier therefore.

For example, in one non-limiting embodiment, R¹ is

ring B is

R² is —CH₂CH₂CH₃, —CH₂CH₂CH₂CH₃, —CH₂CH₂CH(CH₃)₂,

R³ is H, F, Cl, or Br; R⁴ is —CH₃, —CH₂CH₃, —CH₂CH₂CH₃, or —CH₂(CH₃)₂;R⁵ is R⁶; R⁶ is

R⁸ is H, F, Cl, Br, C₁₋₄ allyl, or C(═O)NH₂;

-   R⁹ is

R¹⁰ is H, F, Cl, CN, or —CH₃, or —OCH₃; R^(e) is H or —CH₃.

In another non-limiting embodiment, R¹ is

ring B is

R² is —CH₂CH₂CH₃, —CH₂CH₂CH₂CH₃, —CH₂CH₂CH(CH₃)₂,

R³ is H; R⁴ is —CH₃, —CH₂CH₃, —CH₂CH₂CH₃, or —CH₂(CH₃)₂; R⁵ is R⁶; R⁶ is

R⁸ is H, F, Cl, Br, C₁₋₄ alkyl, or C(═O)NH₂; R⁹ is

R¹⁰ is H, F, Cl, CN, or —CH₃, or —OCH₃; R^(e) is H or —CH₃.

In another non-limiting embodiment, R¹ is

ring B is

R² is —CH₂CH₂CH₃, —CH₂CH₂CH₂CH₃, —CH₂CH₂CH(CH₃)₂,

R³ is H, F, Cl, or Br; R⁴ and R⁹ together form a heterocyclic ringselected from

R⁵ is R⁶;

-   R⁶ is

R⁸ is H, F, Cl, Br, C₁₋₄ alkyl, or C(═O)NH₂; R⁹ is

R¹⁰ is H, F, Cl, CN, or —CH₃, or —OCH₃; R^(e) is H or —CH₃.

In another non-limiting embodiment, R¹ is

ring B is

R² is —CH₂CH₂CH₃, —CH₂CH₂CH₂CH₃, —CH₂CH₂CH(CH₃)₂,

R³ is H; R⁴ and R⁹ together form a heterocyclic ring selected from

R⁵ is R⁶; R⁶ is

R⁸ is H, F, Cl, Br, C₁₋₄ alkyl, or C(═O)NH₂; R⁹ is

R¹⁰ is H, F, Cl, CN, or —CH₃, or —OCH₃; R^(e) is H or —CH₃.

In another non-limiting embodiment, R¹ is

ring A is

R² is —CH₂CH₂CH₃, —CH₂CH₂CH₂CH₃, —CH₂CH₂CH(CH₃)₂,

R³ is H, F, Cl, or Br; R⁴ is —CH₃, —CH₂CH₃, —CH₂CH₂CH₃, or —CH₂(CH₃)₂;R⁵ is R₆; R⁶ is

-   R⁸ is H, F, Cl, Br, C₁₋₄ alkyl, or C(═O)NH₂; R⁹ is

R¹⁰ is H, F, Cl, CN, or —CH₃, or —OCH₃; R^(e) is H or —CH₃.

In another non-limiting embodiment, R¹ is

ring A is

R² is —CH₂CH₂CH₃, —CH₂CH₂CH₂CH₃, —CH₂CH₂CH(CH₃)₂,

R³ is H; R⁴ is —CH₃, —CH₂CH₃, —CH₂CH₂CH₃, or —CH₂(CH₃)₂; R⁵ is R⁶; R⁶ is

R⁸ is H, F, Cl, Br, C₁₋₄ alkyl, or C(═O)NH₂; R⁹ is

R¹⁰ is H, F, Cl, CN, or —CH₃, or —OCH₃;

-   R^(e) is H or —CH₃.

In another non-limiting embodiment, R¹ is

ring A is

R² is —CH₂CH₂CH₃, —CH₂CH₂CH₂CH₃, —CH₂CH₂CH(CH₃)₂,

R³ is H, F, Cl, or Br; R⁴ and R⁹ together form a heterocyclic ringselected from

R⁵ is R⁶; R⁶ is

R⁸ is H, F, Cl, Br, C₁₋₄ alkyl, or C(═O)NH₂; R⁹ is

R¹⁰ is H, F, Cl, CN, or —CH₃, or —OCH₃; R^(e) is H or —CH₃.

In another non-limiting embodiment, R¹ is

ring A is

R² is —CH₂CH₂CH₃, —CH₂CH₂CH₂CH₃, —CH₂CH₂CH(CH₃)₂,

R³ is H; R⁴ and R⁹ together form a heterocyclic ring selected from

R⁵ is R⁶;

-   R⁶ is

R⁸ is H, F, Cl, Br, C₁₋₄ alkyl, or C(═O)NH₂; R⁹ is

R¹⁰ is H, F, Cl, CN, or —CH₃, or —OCH₃; R^(e) is H or —CH₃.

In another embodiment, the compounds of the present invention have EC₅₀values ≤10 μM, using the APJ hcAMP assay disclosed herein, preferably,EC₅₀ values ≤5 μM, more preferably, EC₅₀ values ≤1 μM, even morepreferably, EC₅₀ values ≤0.5 μM, even more preferably, EC₅₀ values ≤0.1μM, even more preferably, EC₅₀ values ≤0.01 μM.

In another aspect, the present invention provides compounds selectedfrom any subset list of compounds exemplified in the presentapplication.

In another aspect, the present invention provides compounds selectedfrom the subset in which the APJ hcAMP EC₅₀ potency range is A.

In another aspect, the present invention provides compounds selectedfrom the subset in which the APJ hcAMP EC₅₀ potency range is B.

In another aspect, the present invention provides compounds selectedfrom the subset in which the APJ hcAMP EC₅₀ potency range is C.

In another aspect, the present invention provides a compound selectedfrom the exemplified examples or a stereoisomer, a tautomer, apharmaceutically acceptable salt, or a solvate thereof.

In another aspect, the present invention provides a compound selectedfrom

(S)-(6-butyl-5-(ethyl(phenyl)amino)-2,4-dihydroxypyridin-3-yl)(3-phenylpyrrolidin-1-yl)methanone,001

(S)-(6-butyl-5-(ethyl(phenyl)amino)-2,4-dihydroxypyridin-3-yl)(3-phenylpyrrolidin-1-yl)methanone,002

1-(4-((6-butyl-5-(ethyl(phenyl)amino)-2,4-dihydroxypyridin-3-yl)sulfonyl)phenyl)-5-methylpyridin-2(1H)-one,003

6-butyl-3-((4-cyclopropylphenyl)sulfonyl)-5-(ethyl(phenyl)amino)pyridine-2,4-diol,004

3-((2-butyl-5-((4-(2-fluoro-3-methylpyridin-4-yl)phenyl)sulfonyl)-4,6-dihydroxypyridin-3-yl)(methyl)amino)benzonitrile,005

(6-butyl-5-((2-fluorophenyl)(methyl)amino)-2,4-dihydroxypyridin-3-yl)(3-(3,5-difluoropyridin-2-yl)pyrrolidin-1-yl)methanone,006

(S)-(6-butyl-2,4-dihydroxy-5-(methyl(phenyl)amino)pyridin-3-yl)(3-phenylpyrrolidin-1-yl)methanone,007

(R)-(6-butyl-2,4-dihydroxy-5-(methyl(phenyl)amino)pyridin-3-yl)(3-phenylpyrrolidin-1-yl)methanone,008

(R)-(6-butyl-2,4-dihydroxy-5-(indolin-1-yl)pyridin-3-yl)(3-phenylpyrrolidin-1-yl)methanone,009

3-((4-bromophenyl)sulfonyl)-6-butyl-5-(methyl(phenyl)amino)pyridine-2,4-diol,010

6-butyl-3-((4-(2-fluoro-3-methylpyridin-4-yl)phenyl)sulfonyl)-5-(methyl(phenyl)amino)pyridine-2,4-diol,011

6-butyl-3-((4-(6-fluoropyridin-3-yl)phenyl)sulfonyl)-5-(methyl(phenyl)amino)pyridine-2,4-diol,012

6-butyl-5-(indolin-1-yl)-3-((4-(3-methylpyridin-4-yl)phenyl)sulfonyl)pyridine-2,4-diol,013

6-butyl-5-(methyl(phenyl)amino)-3-((4-(3-methylpyridin-4-yl)phenyl)sulfonyl)pyridine-2,4-diol,014

6-butyl-3-((4-(6-fluoro-2-methylpyridin-3-yl)phenyl)sulfonyl)-5-(methyl(phenyl)amino)pyridine-2,4-diol,015

6-butyl-3-((4-cyclopropylphenyl)sulfonyl)-5-(methyl(phenyl)amino)pyridine-2,4-diol,016

6-butyl-5-(methyl(phenyl)amino)-3-((4-(2-methylpyridin-3-yl)phenyl)sulfonyl)pyridine-2,4-diol,017

1-(4-((6-butyl-2,4-dihydroxy-5-(methyl(phenyl)amino)pyridin-3-yl)sulfonyl)phenyl)-5-chloropyridin-2(1H)-one,018

(S)-(6-butyl-5-(3,4-dihydroquinolin-1(2H)-yl)-2,4-dihydroxypyridin-3-yl)(3-phenylpyrrolidin-1-yl)methanone,019

6-butyl-3-((4-(2-fluoro-3-methylpyridin-4-yl)phenyl)sulfonyl)-5-isopropyl(phenyl)amino)pyridine-2,4-diol,020

6-butyl-5-(3,4-dihydroquinolin-1(2H)-yl)-3-((4-(6-fluoro-2-methylpyridin-3-yl)phenyl)sulfonyl)pyridine-2,4-diol,021

6-butyl-5-(3,4-dihydroquinolin-1(2H)-yl)-3-((4-(3-methylpyridin-4-yl)phenyl)sulfonyl)pyridine-2,4-diol,022

(R)-(6-butyl-2,4-dihydroxy-5-(isopropyl(phenyl)amino)pyridin-3-yl)(3-phenylpyrrolidin-1-yl)methanone,023

6-butyl-5-(3,4-dihydroquinolin-1(2H)-yl)-3-((4-(2-methylpyridin-3-yl)phenyl)sulfonyl)pyridine-2,4-diol,024

6-butyl-5-(isopropyl(phenyl)amino)-3-((4-(2-methylpyridin-3-yl)phenyl)sulfonyl)pyridine-2,4-diol,025

6-butyl-3-((4-(6-fluoro-2-methylpyridin-3-yl)phenyl)sulfonyl)-5-(isopropyl(phenyl)amino)pyridine-2,4-diol,026

6-butyl-5-(isopropyl(phenyl)amino)-3-((4-(3-methylpyridin-4-yl)phenyl)sulfonyl)pyridine-2,4-diol,027

6-butyl-5-(3,4-dihydroquinolin-1(2H)-yl)-3-((4-(2-fluoro-3-methylpyridin-4-yl)phenyl)sulfonyl)pyridine-2,4-diol,028

6-butyl-3-((4-(2-fluoro-3-methylpyridin-4-yl)phenyl)sulfonyl)-5-((3-methoxyphenyl)(methyl)amino)pyridine-2,4-diol,029

6-butyl-3-((4-(6-fluoro-2-methylpyridin-3-yl)phenyl)sulfonyl)-5-((3-methoxyphenyl)(methyl)amino)pyridine-2,4-diol,030

6-butyl-5-((3-methoxyphenyl)(methyl)amino)-3-((4-(3-methylpyridin-4-yl)phenyl)sulfonyl)pyridine-2,4-diol,031

6-butyl-3-((4-(6-fluoro-2-methylpyridin-3-yl)phenyl)sulfonyl)-5-((4-methoxyphenyl)(methyl)amino)pyridine-2,4-diol,032

6-butyl-5-((4-methoxyphenyl)(methyl)amino)-3-((4-(2-methylpyridin-3-yl)phenyl)sulfonyl)pyridine-2,4-diol,035

(S)-(6-butyl-2,4-dihydroxy-5-((4-methoxyphenyl)(methyl)amino)pyridin-3-yl)(3-phenylpyrrolidin-1-yl)methanone,036

6-butyl-5-((4-methoxyphenyl)(methyl)amino)-3-((4-(3-methylpyridin-4-yl)phenyl)sulfonyl)pyridine-2,4-diol,037

6-butyl-3-((4-(2-fluoro-3-methylpyridin-4-yl)phenyl)sulfonyl)-5-((4-methoxyphenyl)(methyl)amino)pyridine-2,4-diol,038

6-butyl-5-((3-methoxyphenyl)(methyl)amino)-3-((4-(2-methylpyridin-3-yl)phenyl)sulfonyl)pyridine-2,4-diol,039

6-butyl-5-(4-methyl-3,4-dihydroquinolin-1(2H)-yl)-3-((4-(3-methylpyridin-4-yl)phenyl)sulfonyl)pyridine-2,4-diol,040

6-butyl-5-(4-methyl-3,4-dihydroquinolin-1(2H)-yl)-3-((4-((2-methylpyridin-3-yl)phenyl)sulfonyl)pyridine-2,4-diol,042

6-butyl-3-((4-(2-fluoro-3-methylpyridin-4-yl)phenyl)sulfonyl)-5-(4-methyl-3,4-dihydroquinolin-1(2H)-yl)pyridine-2,4-diol,044

(6-butyl-2,4-dihydroxy-5-(4-methyl-3,4-dihydroquinolin-1(2H)-yl)pyridin-3-yl)((S)-3-phenylpyrrolidin-1-yl)methanone,045

6-butyl-5-(2-methyl-3,4-dihydroquinolin-1(2H)-yl)-3-((4-(2-methylpyridin-3-yl)phenyl)sulfonyl)pyridine-2,4-diol,046

6-butyl-3-((4-(2-fluoro-3-methylpyridin-4-yl)phenyl)sulfonyl)-5-(2-methyl-3,4-dihydroquinolin-1(2H)-yl)pyridine-2,4-diol,047

6-butyl-3-((4-(6-fluoro-2-methylpyridin-3-yl)phenyl)sulfonyl)-5-(2-methyl-3,4-dihydroquinolin-1(2H)-yl)pyridine-2,4-diol,048

6-(cyclopropylmethyl)-5-(ethyl(phenyl)amino)-3-((4-(2-fluoro-3-methylpyridin-4-yl)phenyl)sulfonyl)pyridine-2,4-diol,049

6-(cyclopropylmethyl)-5-(ethyl(phenyl)amino)-3-((4-(2-methylpyridin-3-yl)phenyl)sulfonyl)pyridine-2,4-diol,050

6-(cyclopropylmethyl)-5-(ethyl(phenyl)amino)-3-((4-(6-fluoro-2-methylpyridin-3-yl)phenyl)sulfonyl)pyridine-2,4-diol,051

6-(cyclopropylmethyl)-5-(ethyl(phenyl)amino)-3-((4-(3-methylpyridin-4-yl)phenyl)sulfonyl)pyridine-2,4-diol,052

(6-(cyclopropylmethyl)-5-(ethyl(phenyl)amino)-2,4-dihydroxypyridin-3-yl)(3-(3,5-difluoropyridin-2-yl)pyrrolidin-1-yl)methanone,053

4′-((6-butyl-5-(3,4-dihydroquinolin-1(2H)-yl)-2,4-dihydroxypyridin-3-yl)sulfonyl)-N,N-dimethyl-[1,1′-biphenyl]-2-carboxamide,054

4′-((6-(cyclopropylmethyl)-5-(ethyl(phenyl)amino)-2,4-dihydroxypyridin-3-yl)sulfonyl)-N-methyl-[1,1′-biphenyl]-2-carboxamide,055

4′-((5-(ethyl(phenyl)amino)-2,4-dihydroxy-6-(1-methyl-1H-pyrazol-3-yl)pyridin-3-yl)sulfonyl)-N-methyl-[1,1′-biphenyl]-2-carboxamide,056

4′-((6-butyl-5-(3,4-dihydroquinolin-1(2H)-yl)-2,4-dihydroxypyridin-3-yl)sulfonyl)-[1,1′-biphenyl]-2-carboxamide,057

5-(ethyl(phenyl)amino)-6-(1-methyl-1H-pyrazol-3-yl)-3-((4-(2-methylpyridin-3-yl)phenyl)sulfonyl)pyridine-2,4-diol,058

5-(ethyl(phenyl)amino)-3-((4-(6-fluoro-2-methylpyridin-3-yl)phenyl)sulfonyl)-6-(1-methyl-1H-pyrazol-3-yl)pyridine-2,4-diol,059

4′-((5-(ethyl(phenyl)amino)-2,4-dihydroxy-6-(1-methyl-1H-pyrazol-3-yl)pyridin-3-yl)sulfonyl)-N,N-dimethyl-[1,1′-biphenyl]-2-carboxamide,060

4′-((6-butyl-5-(3,4-dihydroquinolin-1(2H)-yl)-2,4-dihydroxypyridin-3-yl)sulfonyl)-N-methyl-[1,1′-biphenyl]-2-carboxamide,061

4′-((6-(cyclopropylmethyl)-5-(ethyl(phenyl)amino)-2,4-dihydroxypyridin-3-yl)sulfonyl)-N,N-dimethyl-[1,1′-biphenyl]-2-carboxamide,062

5-(ethyl(phenyl)amino)-3-((4-(2-fluoro-3-methylpyridin-4-yl)phenyl)sulfonyl)-6-(1-methyl-1H-pyrazol-3-yl)pyridine-2,4-diol,063

5-(ethyl(phenyl)amino)-6-(1-methyl-1H-pyrazol-3-yl)-3-((4-(3-methylpyridin-4-yl)phenyl)sulfonyl)pyridine-2,4-diol,064

4′-((6-butyl-2,4-dihydroxy-5-(methyl(phenyl)amino)pyridin-3-yl)sulfonyl)-[1,1′-biphenyl]-2-carboxamide,065

(R)-(6-butyl-5-(ethyl(phenyl)amino)-2,4-dihydroxypyridin-3-yl)(3-phenylpyrrolidin-1-yl)methanone,066

(6-butyl-5-(ethyl(phenyl)amino)-2,4-dihydroxypyridin-3-yl)(3-(5-chloropyridin-2-yl)pyrrolidin-1-yl)methanone,067

(S)-(6-butyl-2,4-dihydroxy-5-(phenyl(propyl)amino)pyridin-3-yl)(3-phenylpyrrolidin-1-yl)methanone,068

(R)-(6-butyl-2,4-dihydroxy-5-(phenyl(propyl)amino)pyridin-3-yl)(3-phenylpyrrolidin-1-yl)methanone,069

(6-butyl-5-(ethyl(phenyl)amino)-2,4-dihydroxypyridin-3-yl)(3-(5-chloro-3-fluoropyridin-2-yl)pyrrolidin-1-yl)methanone,070

(6-butyl-5-(ethyl(phenyl)amino)-2,4-dihydroxypyridin-3-yl)(3-(3,5-difluoropyridin-2-yl)pyrrolidin-1-yl)methanone,071

(6-butyl-5-(ethyl(phenyl)amino)-2,4-dihydroxypyridin-3-yl)(3-(5-chloro-3-fluoropyridin-2-yl)pyrrolidin-1-yl)methanone,072

(6-butyl-5-(ethyl(phenyl)amino)-2,4-dihydroxypyridin-3-yl)(3-(3,5-difluoropyridin-2-yl)pyrrolidin-1-yl)methanone,073

(6-butyl-5-(ethyl(phenyl)amino)-2,4-dihydroxypyridin-3-yl)(4-(2,3-dichlorobenzyl)piperazin-1-yl)methanone,074

(6-butyl-5-(ethyl(phenyl)amino)-2,4-dihydroxypyridin-3-yl)(3-(2-fluorophenyl)pyrrolidin-1-yl)methanone,075

(6-butyl-5-(ethyl(phenyl)amino)-2,4-dihydroxypyridin-3-yl)(3-(5-chloropyridin-2-yl)pyrrolidin-1-yl)methanone,076

3-((4-bromophenyl)sulfonyl)-6-butyl-5-(ethyl(phenyl)amino)pyridine-2,4-diol,077

6-butyl-5-(ethyl(phenyl)amino)-3-((4-(3-methylpyridin-4-yl)phenyl)sulfonyl)pyridine-2,4-diol,078

6-butyl-5-(ethyl(phenyl)amino)-3-((4-(2-methylpyridin-3-yl)phenyl)sulfonyl)pyridine-2,4-diol,079

6-butyl-5-(ethyl(phenyl)amino)-3-((4-(2-fluoro-3-methylpyridin-4-yl)phenyl)sulfonyl)pyridine-2,4-diol,080

6-butyl-5-(ethyl(phenyl)amino)-3-((4-(2-methoxypyridin-4-yl)phenyl)sulfonyl)pyridine-2,4-diol,081

1-(4-((6-butyl-5-(ethyl(phenyl)amino)-2,4-dihydroxypyridin-3-yl)sulfonyl)phenyl)-5-chloropyridin-2(1H)-one,082

4′-((6-butyl-5-(ethyl(phenyl)amino)-2,4-dihydroxypyridin-3-yl)sulfonyl)-[1,1′-biphenyl]-2-carbonitrile,083

6-butyl-5-(ethyl(phenyl)amino)-3-(phenylsulfonyl)pyridine-2,4-diol, 084

4′-((6-butyl-5-(ethyl(phenyl)amino)-2,4-dihydroxypyridin-3-yl)sulfonyl)-[1,1′-biphenyl]-2-carboxamide,085

6-butyl-5-(ethyl(phenyl)amino)-3-((4-(6-fluoro-2-methylpyridin-3-yl)phenyl)sulfonyl)pyridine-2,4-diol,086

6-butyl-5-(ethyl(phenyl)amino)-3-((2′-(methoxymethyl)-[1,1′-biphenyl]-4-yl)sulfonyl)pyridine-2,4-diol,087

3-([1,1′-biphenyl]-4-ylsulfonyl)-6-butyl-5-(ethyl(phenyl)amino)pyridine-2,4-diol,088

6-butyl-5-(methyl(m-tolyl)amino)-3-((4-(3-methylpyridin-4-yl)phenyl)sulfonyl)pyridine-2,4-diol,090

6-butyl-3-((4-(2-fluoro-3-methylpyridin-4-yl)phenyl)sulfonyl)-5-(methyl(m-tolyl)amino)pyridine-2,4-diol,091

6-butyl-3-((4-(2-fluoro-3-methylpyridin-4-yl)phenyl)sulfonyl)-5-(methyl(p-tolyl)amino)pyridine-2,4-diol,092

3-((4-bromophenyl)sulfonyl)-6-butyl-5-(methyl(m-tolyl)amino)pyridine-2,4-diol,093

6-butyl-5-(methyl(p-tolyl)amino)-3-((4-(3-methylpyridin-4-yl)phenyl)sulfonyl)pyridine-2,4-diol,094

6-butyl-3-((4-(6-fluoro-2-methylpyridin-3-yl)phenyl)sulfonyl)-5-(methyl(m-tolyl)amino)pyridine-2,4-diol,095

6-butyl-5-(methyl(m-tolyl)amino)-3-((4-(2-methylpyridin-3-yl)phenyl)sulfonyl)pyridine-2,4-diol,096

6-butyl-5-(methyl(p-tolyl)amino)-3-((4-(2-methylpyridin-3-yl)phenyl)sulfonyl)pyridine-2,4-diol,097

1-(4-((6-butyl-2,4-dihydroxy-5-(methyl(p-tolyl)amino)pyridin-3-yl)sulfonyl)phenyl)-5-methylpyridin-2(1H)-one,098

1-(4-((6-butyl-2,4-dihydroxy-5-(methyl(m-tolyl)amino)pyridin-3-yl)sulfonyl)phenyl)-5-methylpyridin-2(1H)-one,099

6-butyl-3-((4-cyclopropylphenyl)sulfonyl)-5-(methyl(p-tolyl)amino)pyridine-2,4-diol,100

6-butyl-5-((3-fluorophenyl)(methyl)amino)-3-((4-(2-methylpyridin-3-yl)phenyl)sulfonyl)pyridine-2,4-diol,101

6-butyl-5-((3-chlorophenyl)(methyl)amino)-3-((4-(2-methylpyridin-3-yl)phenyl)sulfonyl)pyridine-2,4-diol,102

6-butyl-5-((4-chlorophenyl)(methyl)amino)-3-((4-(2-fluoro-3-methylpyridin-4-yl)phenyl)sulfonyl)pyridine-2,4-diol,103

6-butyl-5-((3-fluorophenyl)(methyl)amino)-3-((4-(3-methylpyridin-4-yl)phenyl)sulfonyl)pyridine-2,4-diol,104

6-butyl-5-((3-chlorophenyl)(methyl)amino)-3-((4-(6-fluoro-2-methylpyridin-3-yl)phenyl)sulfonyl)pyridine-2,4-diol,105

6-butyl-3-((4-(2-fluoro-3-methylpyridin-4-yl)phenyl)sulfonyl)-5-((3-fluorophenyl)(methyl)amino)pyridine-2,4-diol,106

6-butyl-5-((3-chlorophenyl)(methyl)amino)-3-((4-(2-fluoro-3-methylpyridin-4-yl)phenyl)sulfonyl)pyridine-2,4-diol,107

6-butyl-5-((4-chlorophenyl)(methyl)amino)-3-((4-(3-methylpyridin-4-yl)phenyl)sulfonyl)pyridine-2,4-diol,108

6-butyl-3-((4-(6-fluoro-2-methylpyridin-3-yl)phenyl)sulfonyl)-5-((3-fluorophenyl)(methyl)amino)pyridine-2,4-diol,109

6-butyl-5-((3-chlorophenyl)(methyl)amino)-3-((4-(3-methylpyridin-4-yl)phenyl)sulfonyl)pyridine-2,4-diol,110

6-butyl-5-((4-chlorophenyl)(methyl)amino)-3-((4-(2-methylpyridin-3-yl)phenyl)sulfonyl)pyridine-2,4-diol,111

6-butyl-5-((2-fluorophenyl)(methyl)amino)-3-((4-(3-methylpyridin-4-yl)phenyl)sulfonyl)pyridine-2,4-diol,112

3-((2-butyl-4,6-dihydroxy-5-((4-(3-methylpyridin-4-yl)phenyl)sulfonyl)pyridin-3-yl)(methyl)amino)benzonitrile,113

5-(ethyl(phenyl)amino)-3-((4-(6-fluoro-2-methylpyridin-3-yl)phenyl)sulfonyl)-6-(m-tolyl)pyridine-2,4-diol,114

6-butyl-5-(3,4-dihydrobenzo[b][1,4]oxazepin-5(2H)-yl)-3-((4-(6-fluoro-2-methylpyridin-3-yl)phenyl)sulfonyl)pyridine-2,4-diol,115

6-butyl-3-((4-(3-methylpyridin-4-yl)phenyl)sulfonyl)-5-(2-phenylpiperidin-1-yl)pyridine-2,4-diol,116

3-((2-butyl-5-((4-(6-fluoro-2-methylpyridin-3-yl)phenyl)sulfonyl)-4,6-dihydroxypyridin-3-yl)(methyl)amino)benzonitrile,117

6-butyl-3-((4-(6-fluoro-2-methylpyridin-3-yl)phenyl)sulfonyl)-5-((2-fluorophenyl)(methyl)amino)pyridine-2,4-diol,118

3-((2-butyl-4,6-dihydroxy-5-((4-(2-methylpyridin-3-yl)phenyl)sulfonyl)pyridin-3-yl)(methyl)amino)benzonitrile,119

5-(ethyl(phenyl)amino)-3-((4-(3-methylpyridin-4-yl)phenyl)sulfonyl)-6-(m-tolyl)pyridine-2,4-diol,120

5-(ethyl(phenyl)amino)-3-((4-(2-fluoro-3-methylpyridin-4-yl)phenyl)sulfonyl)-6-(m-tolyl)pyridine-2,4-diol,122

6-butyl-5-(3,4-dihydrobenzo[b][1,4]oxazepin-5(2H)-yl)-3-((4-(2-methylpyridin-3-yl)phenyl)sulfonyl)pyridine-2,4-diol,123

6-butyl-5-((2-fluorophenyl)(methyl)amino)-3-((4-(2-methylpyridin-3-yl)phenyl)sulfonyl)pyridine-2,4-diol,124

6-butyl-3-((4-(2-fluoro-3-methylpyridin-4-yl)phenyl)sulfonyl)-5-((2-fluorophenyl)(methyl)amino)pyridine-2,4-diol,125

6-butyl-3-((4-(6-fluoro-2-methylpyridin-3-yl)phenyl)sulfonyl)-5-(2-phenylpiperidin-1-yl)pyridine-2,4-diol,126

6-butyl-5-(3,4-dihydrobenzo[b][1,4]oxazepin-5(2H)-yl)-3-((4-(2-fluoro-3-methylpyridin-4-yl)phenyl)sulfonyl)pyridine-2,4-diol,127

6-butyl-3-((4-(2-fluoro-3-methylpyridin-4-yl)phenyl)sulfonyl)-5-(2-phenylpiperidin-1-yl)pyridine-2,4-diol,128

6-butyl-5-(3,4-dihydrobenzo[b][1,4]oxazepin-5(2H)-yl)-3-((4-(3-methylpyridin-4-yl)phenyl)sulfonyl)pyridine-2,4-diol,129

(3-(3,5-difluoropyridin-2-yl)pyrrolidin-1-yl)(5-(ethyl(phenyl)amino)-2,4-dihydroxy-6-(m-tolyl)pyridin-3-yl)methanone,130

3-((4-bromophenyl)sulfonyl)-5-(ethyl(phenyl)amino)-6-(m-tolyl)pyridine-2,4-diol,131

(3-(3,5-difluoropyridin-2-yl)pyrrolidin-1-yl)(5-(ethyl(phenyl)amino)-2,4-dihydroxy-6-(m-tolyl)pyridin-3-yl)methanone,132

6-butyl-5-((3,5-dimethylphenyl)(ethyl)amino)-3-((4-(3-methylpyridin-4-yl)phenyl)sulfonyl)pyridine-2,4-diol,133

3-((4-bromophenyl)sulfonyl)-6-butyl-5-((3,5-dimethylphenyl)(ethyl)amino)pyridine-2,4-diol,134

6-butyl-5-((3,5-dimethylphenyl)(ethyl)amino)-3-((4-(6-fluoro-2-methylpyridin-3-yl)phenyl)sulfonyl)pyridine-2,4-diol,135

6-butyl-5-((3,5-dimethylphenyl)(ethyl)amino)-3-((4-(2-fluoro-3-methylpyridin-4-yl)phenyl)sulfonyl)pyridine-2,4-diol,136

4′-((6-butyl-5-((3-cyanophenyl)(methyl)amino)-2,4-dihydroxypyridin-3-yl)sulfonyl)-N-methyl-[1,1′-biphenyl]-2-carboxamide,137

4′-((6-butyl-5-((3-cyanophenyl)(methyl)amino)-2,4-dihydroxypyridin-3-yl)sulfonyl)-[1,1′-biphenyl]-2-carboxamide,138

4′-((6-butyl-5-((3-cyanophenyl)(methyl)amino)-2,4-dihydroxypyridin-3-yl)sulfonyl)-N,N-dimethyl-[1,1′-biphenyl]-2-carboxamide,139

4′-((6-butyl-5-((3,5-dimethylphenyl)(ethyl)amino)-2,4-dihydroxypyridin-3-yl)sulfonyl)-N,N-dimethyl-[1,1′-biphenyl]-2-carboxamide,140

4′-((5-(ethyl(phenyl)amino)-2,4-dihydroxy-6-(m-tolyl)pyridin-3-yl)sulfonyl)-N,N-dimethyl-[1,1′-biphenyl]-2-carboxamide,141

4′-((6-butyl-5-(3,4-dihydrobenzo[b][1,4]oxazepin-5(2H)-yl)-2,4-dihydroxypyridin-3-yl)sulfonyl)-N,N-dimethyl-[1,1′-biphenyl]-2-carboxamide,142

4′-((6-butyl-5-((3,5-dimethylphenyl)(ethyl)amino)-2,4-dihydroxypyridin-3-yl)sulfonyl)-[1,1′-biphenyl]-2-carboxamide,143

4′-((5-(ethyl(phenyl)amino)-2,4-dihydroxy-6-(m-tolyl)pyridin-3-yl)sulfonyl)-[1,1′-biphenyl]-2-carboxamide,144

4′-((5-(ethyl(phenyl)amino)-2,4-dihydroxy-6-(m-tolyl)pyridin-3-yl)sulfonyl)-N-methyl-[1,1′-biphenyl]-2-carboxamide,145

4′-((6-butyl-5-(3,4-dihydrobenzo[b][1,4]oxazepin-5(2H)-yl)-2,4-dihydroxypyridin-3-yl)sulfonyl)-N-methyl-[1,1′-biphenyl]-2-carboxamide,146

II. OTHER EMBODIMENTS OF THE INVENTION

In another embodiment, the present invention provides a compositioncomprising at least one of the compounds of the present invention or astereoisomer, a tautomer, a pharmaceutically acceptable salt, or asolvate thereof.

In another embodiment, the present invention provides a pharmaceuticalcomposition comprising a pharmaceutically acceptable carrier and atleast one of the compounds of the present invention or a stereoisomer, atautomer, a pharmaceutically acceptable salt, or a solvate thereof.

In another embodiment, the present invention provides a pharmaceuticalcomposition, comprising a pharmaceutically acceptable carrier and atherapeutically effective amount of at least one of the compounds of thepresent invention or a stereoisomer, a tautomer, a pharmaceuticallyacceptable salt, or a solvate thereof.

In another embodiment, the present invention provides a process formaking a compound of the present invention or a stereoisomer, atautomer, a pharmaceutically acceptable salt, or a solvate thereof.

In another embodiment, the present invention provides an intermediatefor making a compound of the present invention or a stereoisomer, atautomer, a pharmaceutically acceptable salt, or a solvate thereof.

The present invention provides a pharmaceutical composition furthercomprising additional therapeutic agent(s). In a preferred embodiment,the present invention provides pharmaceutical composition, wherein theadditional therapeutic agent is, for example, angiotensin convertingenzyme (ACE) inhibitor, β-adrenergic receptor blocker, angiotensin IIreceptor blocker, diuretic, aldosterone antagonist and digitaliscompound.

In another embodiment, the present invention provides a method for thetreatment and/or prophylaxis of multiple diseases or disordersassociated with APJ or apelin activity, comprising administering to apatient in need of such treatment and/or prophylaxis a therapeuticallyeffective amount of at least one of the compounds of the presentinvention, alone, or, optionally, in combination with another compoundof the present invention and/or at least one other type of therapeuticagent.

Examples of diseases or disorders associated with the activity of theAPJ and apelin that can be prevented, modulated, or treated according tothe present invention include, but are not limited to heart failure suchas acute decompensated heart failure (ADHF), atrial fibrillation,coronary artery disease, peripheral vascular disease, atherosclerosis,diabetes, metabolic syndrome, hypertension, pulmonary hypertension,cerebrovascular disorders and the sequelae thereof, cardiovasculardisorders, angina, ischemia, stroke, myocardial infarction, acutecoronary syndrome, reperfusion injury, angioplastic restenosis, vascularcomplications of diabetes and obesity.

In another embodiment, the present invention provides a method for thetreatment and/or prophylaxis of heart failure, coronary artery disease,peripheral vascular disease, atherosclerosis, diabetes, metabolicsyndrome, hypertension, pulmonary hypertension, atrial fibrillation,angina, ischemia, stroke, myocardial infarction, acute coronarysyndrome, reperfusion injury, angioplastic restenosis, vascularcomplications of diabetes, obesity, comprising administering to apatient in need of such treatment and/or prophylaxis a therapeuticallyeffective amount of at least one of the compounds of the presentinvention, alone, or, optionally, in combination with another compoundof the present invention and/or at least one other type of therapeuticagent.

In another embodiment, the present invention provides a method for thetreatment and/or prophylaxis of heart failure such as ADHF, comprisingadministering to a patient in need of such treatment and/or prophylaxisa therapeutically effective amount of at least one of the compounds ofthe present invention, alone, or, optionally, in combination withanother compound of the present invention and/or at least one other typeof therapeutic agent.

In another embodiment, the present invention provides a method for thetreatment and/or prophylaxis of diabetes and obesity, comprisingadministering to a patient in need of such treatment and/or prophylaxisa therapeutically effective amount of at least one of the compounds ofthe present invention, alone, or, optionally, in combination withanother compound of the present invention and/or at least one other typeof therapeutic agent.

In another embodiment, the present invention provides a method for thetreatment and/or prophylaxis of hypertension, comprising administeringto a patient in need of such treatment and/or prophylaxis atherapeutically effective amount of at least one of the compounds of thepresent invention, alone, or, optionally, in combination with anothercompound of the present invention and/or at least one other type oftherapeutic agent.

In another embodiment, the present invention provides a method for thetreatment and/or prophylaxis of pulmonary hypertension, comprisingadministering to a patient in need of such treatment and/or prophylaxisa therapeutically effective amount of at least one of the compounds ofthe present invention, alone, or, optionally, in combination withanother compound of the present invention and/or at least one other typeof therapeutic agent.

In another embodiment, the present invention provides a method for thetreatment and/or prophylaxis of acute coronary syndrome and cardiacischemia, comprising administering to a patient in need of suchtreatment and/or prophylaxis a therapeutically effective amount of atleast one of the compounds of the present invention, alone, or,optionally, in combination with another compound of the presentinvention and/or at least one other type of therapeutic agent.

In another embodiment, the present invention provides a compound of thepresent invention for use in therapy.

In another embodiment, the present invention provides a compound of thepresent invention for use in therapy for the treatment and/orprophylaxis of multiple diseases or disorders associated with APJ andapelin.

In another embodiment, the present invention also provides the use of acompound of the present invention for the manufacture of a medicamentfor the treatment and/or prophylaxis of multiple diseases or disordersassociated with APJ and apelin.

In another embodiment, the present invention provides a method for thetreatment and/or prophylaxis of multiple diseases or disordersassociated with APJ and apelin, comprising administering to a patient inneed thereof a therapeutically effective amount of a first and secondtherapeutic agent, wherein the first therapeutic agent is a compound ofthe present invention. Preferably, the second therapeutic agent, forexample selected inotropic agent such as β-adrenergic agonist (forexample dobutamine).

In another embodiment, the present invention provides a combinedpreparation of a compound of the present invention and additionaltherapeutic agent(s) for simultaneous, separate or sequential use intherapy.

In another embodiment, the present invention provides a combinedpreparation of a compound of the present invention and additionaltherapeutic agent(s) for simultaneous, separate or sequential use in thetreatment and/or prophylaxis of multiple diseases or disordersassociated with APJ and apelin.

Where desired, the compound of the present invention may be used incombination with one or more other types of cardiovascular agents and/orone or more other types of therapeutic agents which may be administeredorally in the same dosage form, in a separate oral dosage form or byinjection. The other type of cardiovascular agents that may beoptionally employed in combination with the APJ agonist of the presentinvention may be one, two, three or more cardiovascular agentsadministered orally in the same dosage form, in a separate oral dosageform, or by injection to produce an additional pharmacological benefit.

The compounds of the present invention may be employed in combinationwith additional therapeutic agent(s) selected from one or more,preferably one to three, of the following therapeutic agents:anti-hypertensive agents, ACE inhibitors, mineralocorticoid receptorantagonists, angiotensin receptor blockers, calcium channel blockers,β-adrenergic receptor blockers, diuretics, vasorelaxation agents such asnitrates, anti-atherosclerotic agents, anti-dyslipidemic agents,anti-diabetic agents, anti-hyperglycemic agents, anti-hyperinsulinemicagents, anti-thrombotic agents, anti-retinopathic agents,anti-neuropathic agents, anti-nephropathic agents, anti-ischemic agents,calcium channel blockers, anti-obesity agents, anti-hyperlipidemicagents, anti-hypertriglyceridemic agents, anti-hypercholesterolemicagents, anti-restenotic agents, anti-pancreatic agents, lipid loweringagents, anorectic agents, memory enhancing agents, anti-dementia agents,cognition promoting agents, appetite suppressants, agents for treatingheart failure, agents for treating peripheral arterial disease, agentsfor treating malignant tumors, and anti-inflammatory agents.

In another embodiment, additional therapeutic agent(s) used in combinedpharmaceutical compositions or combined methods or combined uses, areselected from one or more, preferably one to three, of the followingtherapeutic agents in treating heart failure: ACE inhibitors,β-blockers, diuretics, mineralocorticoid receptor antagonists, renininhibitors, calcium channel blockers, angiotensin II receptorantagonists, nitrates, digitalis compounds, inotropic agents.

The present invention may be embodied in other specific forms withoutparting from the spirit or essential attributes thereof. This inventionencompasses all combinations of preferred aspects of the invention notedherein. It is understood that any and all embodiments of the presentinvention may be taken in conjunction with any other embodiment orembodiments to describe additional embodiments. It is also understoodthat each individual element of the embodiments is its own independentembodiment. Furthermore, any element of an embodiment is meant to becombined with any and all other elements from any embodiment to describean additional embodiment.

III. CHEMISTRY

Throughout the specification and the appended claims, a given chemicalformula or name shall encompass all stereo and optical isomers andracemates thereof where such isomers exist. Unless otherwise indicated,all chiral (enantiomeric and diastereomeric) and racemic forms arewithin the scope of the invention. Many geometric isomers of C═C doublebonds, C═N double bonds, ring systems, and the like can also be presentin the compounds, and all such stable isomers are contemplated in thepresent invention. Cis- and trans- (or E- and Z-) geometric isomers ofthe compounds of the present invention are described and may be isolatedas a mixture of isomers or as separated isomeric forms. The presentcompounds can be isolated in optically active or racemic forms.Optically active forms may be prepared by resolution of racemic forms orby synthesis from optically active starting materials. All processesused to prepare compounds of the present invention and intermediatesmade therein are considered to be part of the present invention. Whenenantiomeric or diastereomeric products are prepared, they may beseparated by conventional methods, for example, by chromatography orfractional crystallization. Depending on the process conditions the endproducts of the present invention are obtained either in free (neutral)or salt form. Both the free form and the salts of these end products arewithin the scope of the invention. If so desired, one form of a compoundmay be converted into another form. A free base or acid may be convertedinto a salt; a salt may be converted into the free compound or anothersalt; a mixture of isomeric compounds of the present invention may beseparated into the individual isomers. Compounds of the presentinvention, free form and salts thereof, may exist in multiple tautomericforms, in which hydrogen atoms are transposed to other parts of themolecules and the chemical bonds between the atoms of the molecules areconsequently rearranged. It should be understood that all tautomericforms, insofar as they may exist, are included within the invention.

As used herein, the term “alkyl” or “alkylene” is intended to includeboth branched and straight-chain saturated aliphatic hydrocarbon groupshaving the specified number of carbon atoms. For examples, “C₁ to C₁₂alkyl” or “C₁₋₁₂ alkyl” (or alkylene), is intended to include C₁, C₂,C₃, C₄, C₅, C₆, C₇, C₈, C₉, C₁₀, C₁₁ and C₁₂ alkyl groups; “C₄ to C₁₈alkyl” or “C₄₋₁₈ alkyl” (or alkylene), is intended to include C₄, C₅,C₆, C₇, C₈, C₉, C₁₀, C₁₁, C₁₂, C₁₃, C₁₄, C₁₅, C₁₆, C₁₇, and C₁₈ alkylgroups. Additionally, for example, “C₁ to C₆ alkyl” or “C₁₋₆ alkyl”denotes alkyl having 1 to 6 carbon atoms. Alkyl group can beunsubstituted or substituted with at least one hydrogen being replacedby another chemical group. Example alkyl groups include, but are notlimited to, methyl (Me), ethyl (Et), propyl (e.g., n-propyl andisopropyl), butyl (e.g., n-butyl, isobutyl, t-butyl), and pentyl (e.g.,n-pentyl, isopentyl, neopentyl). When “C₀ alkyl” or “C₀ alkylene” isused, it is intended to denote a direct bond.

“Alkenyl” or “alkenylene” is intended to include hydrocarbon chains ofeither straight or branched configuration having the specified number ofcarbon atoms and one or more, preferably one to two, carbon-carbondouble bonds that may occur in any stable point along the chain. Forexample, “C₂ to C₆ alkenyl” or “C₂₋₆ alkenyl” (or alkenylene), isintended to include C₂, C₃, C₄, C₅, and C₆ alkenyl groups. Examples ofalkenyl include, but are not limited to, ethenyl, 1-propenyl,2-propenyl, 2-butenyl, 3-butenyl, 2-pentenyl, 3, pentenyl, 4-pentenyl,2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 2-methyl-2-propenyl, and4-methyl-3-pentenyl.

“Alkynyl” or “alkynylene” is intended to include hydrocarbon chains ofeither straight or branched configuration having one or more, preferablyone to three, carbon-carbon triple bonds that may occur in any stablepoint along the chain. For example, “C₂ to C₆ alkynyl” or “C₂₋₆ alkynyl”(or alkynylene), is intended to include C₂, C₃, C₄, C₅, and C₆ alkynylgroups; such as ethynyl, propynyl, butynyl, pentynyl and hexynyl.

When the term “hydrocarbon chain” is used, it is intended to include“alkyl”, “alkenyl” and “alkynyl”, unless otherwise specified.

The term “alkoxy” or “alkyloxy” refers to an —O-alkyl group. Forexample, “C₁ to C₆ alkoxy” or “C₁₋₆ alkoxy” (or alkyloxy), is intendedto include C₁, C₂, C₃, C₄, C₅, and C₆ alkoxy groups. Example alkoxygroups include, but are not limited to, methoxy, ethoxy, propoxy (e.g.,n-propoxy and isopropoxy), and t-butoxy. Similarly, “alkylthio” or“thioalkoxy” represents an alkyl group as defined above with theindicated number of carbon atoms attached through a sulphur bridge; forexample methyl-S— and ethyl-S—.

“Halo” or “halogen” includes fluoro, chloro, bromo, and iodo.“Haloalkyl” is intended to include both branched and straight-chainsaturated aliphatic hydrocarbon groups having the specified number ofcarbon atoms, substituted with 1 or more halogens. Examples of haloalkylinclude, but are not limited to, fluoromethyl, difluoromethyl,trifluoromethyl, trichloromethyl, pentafluoroethyl, pentachloroethyl,2,2,2-trifluoroethyl, heptafluoropropyl, and heptachloropropyl. Examplesof haloalkyl also include “fluoroalkyl” that is intended to include bothbranched and straight-chain saturated aliphatic hydrocarbon groupshaving the specified number of carbon atoms, substituted with 1 or morefluorine atoms.

“Haloalkoxy” or “haloalkyloxy” represents a haloalkyl group as definedabove with the indicated number of carbon atoms attached through anoxygen bridge. For example, “C₁₋₆ haloalkoxy”, is intended to includeC₁, C₂, C₃, C₄, C₅, and C₆ haloalkoxy groups. Examples of haloalkoxyinclude, but are not limited to, trifluoromethoxy,2,2,2-trifluoroethoxy, and pentafluorothoxy. Similarly, “haloalkylthio”or “thiohaloalkoxy” represents a haloalkyl group as defined above withthe indicated number of carbon atoms attached through a sulphur bridge;for example trifluoromethyl-S—, and pentafluoroethyl-S—.

The term “cycloalkyl” refers to cyclized alkyl groups, including mono-,bi- or poly-cyclic ring systems. For example, “C₃ to C₆ cycloalkyl” or“C₃₋₆ cycloalkyl” is intended to include C₃, C₄, C₅, and C₆ cycloalkylgroups. Example cycloalkyl groups include, but are not limited to,cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and norbornyl.Branched cycloalkyl groups such as 1-methylcyclopropyl and2-methylcyclopropyl are included in the definition of “cycloalkyl”. Theterm “cycloalkenyl” refers to cyclized alkenyl groups. C₄₋₆ cycloalkenylis intended to include C₄, C₅, and C₆ cycloalkenyl groups. Examplecycloalkenyl groups include, but are not limited to, cyclobutenyl,cyclopentenyl, and cyclohexenyl.

As used herein, “carbocycle”, “carbocyclyl”, or “carbocyclic residue” isintended to mean any stable 3-, 4-, 5-, 6-, 7-, or 8-membered monocyclicor bicyclic or 7-, 8-, 9-, 10-, 11-, 12-, or 13-membered bicyclic ortricyclic hydrocarbon ring, any of which may be saturated, partiallyunsaturated, unsaturated or aromatic. Examples of such carbocyclesinclude, but are not limited to, cyclopropyl, cyclobutyl, cyclobutenyl,cyclopentyl, cyclopentenyl, cyclohexyl, cycloheptenyl, cycloheptyl,cycloheptenyl, adamantyl, cyclooctyl, cyclooctenyl, cyclooctadienyl,[3.3.0]bicyclooctane, [4.3.0]bicyclononane, [4.4.0]bicyclodecane(decalin), [2.2.2]bicyclooctane, fluorenyl, phenyl, naphthyl, indanyladamantyl, anthracenyl, and tetrahydronaphthyl (tetralin). As shownabove, bridged rings are also included in the definition of carbocycle(e.g., [2.2.2]bicyclooctane). Preferred carbocycles, unless otherwisespecified, are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl,indanyl, and tetrahydronaphthyl. When the term “carbocycle” is used, itis intended to include “aryl.” A bridged ring occurs when one or more,preferably one to three, carbon atoms link two non-adjacent carbonatoms. Preferred bridges are one or two carbon atoms. It is noted that abridge always converts a monocyclic ring into a tricyclic ring. When aring is bridged, the substituents recited for the ring may also bepresent on the bridge.

As used herein, the term “bicyclic carbocycle” or “bicyclic carbocyclicgroup” is intended to mean a stable 9- or 10-membered carbocyclic ringsystem that contains two fused rings and consists of carbon atoms. Ofthe two fused rings, one ring is a benzo ring fused to a second ring;and the second ring is a 5- or 6-membered carbon ring which issaturated, partially unsaturated, or unsaturated. The bicycliccarbocyclic group may be attached to its pendant group at any carbonatom which results in a stable structure. The bicyclic carbocyclic groupdescribed herein may be substituted on any carbon if the resultingcompound is stable. Examples of a bicyclic carbocyclic group are, butnot limited to, naphthyl, 1,2-dihydronaphthyl,1,2,3,4-tetrahydronaphthyl, and indanyl.

“Aryl” groups refer to monocyclic or bicyclic aromatic hydrocarbons,including, for example, phenyl, and naphthyl. Aryl moieties are wellknown and described, for example, in Lewis, R. J., ed., Hawley'sCondensed Chemical Dictionary, 15th Edition, John Wiley & Sons, Inc.,New York (2007). “C₆₋₁₀ aryl” refers to phenyl and naphthyl.

The term “benzyl”, as used herein, refers to a methyl group on which oneof the hydrogen atoms is replaced by a phenyl group.

As used herein, the term “heterocycle”, “heterocyclyl”, or “heterocyclicgroup” is intended to mean a stable 3-, 4-, 5-, 6-, or 7-memberedmonocyclic or bicyclic or 7-, 8-, 9-, 10-, 11-, 12-, 13-, or 14-memberedpolycyclic heterocyclic ring that is saturated, partially unsaturated,or fully unsaturated, and that contains carbon atoms and 1, 2, 3 or 4heteroatoms independently selected from the group consisting of N, O andS; and including any polycyclic group in which any of the above-definedheterocyclic rings is fused to a benzene ring. The nitrogen and sulfurheteroatoms may optionally be oxidized (i.e., N→O and S(O)_(p), whereinp is 0, 1 or 2). The nitrogen atom may be substituted or unsubstituted(i.e., N or NR wherein R is H or another substituent, if defined). Theheterocyclic ring may be attached to its pendant group at any heteroatomor carbon atom that results in a stable structure. The heterocyclicrings described herein may be substituted on carbon or on a nitrogenatom if the resulting compound is stable. A nitrogen in the heterocyclemay optionally be quaternized. It is preferred that when the totalnumber of S and O atoms in the heterocycle exceeds 1, then theseheteroatoms are not adjacent to one another. It is preferred that thetotal number of S and O atoms in the heterocycle is not more than 1.When the term “heterocycle” is used, it is intended to includeheteroaryl.

Examples of heterocycles include, but are not limited to, acridinyl,azetidinyl, azocinyl, benzimidazolyl, benzofuranyl, benzothiofuranyl,benzothiophenyl, benzoxazolyl, benzoxazolinyl, benzthiazolyl,benztriazolyl, benztetrazolyl, benzisoxazolyl, benzisothiazolyl,benzimidazolinyl, carbazolyl, 4aH-carbazolyl, carbolinyl, chromanyl,chromenyl, cinnolinyl, decahydroquinolinyl, 2H,6H-1,5,2-dithiazinyl,dihydrofuro[2,3-b]tetrahydrofuran, furanyl, furazanyl, imidazolidinyl,imidazolinyl, imidazolyl, 1H-indazolyl, imidazolopyridinyl, indolenyl,indolinyl, indolizinyl, indolyl, 3H-indolyl, isatinoyl, isobenzofuranyl,isochromanyl, isoindazolyl, isoindolinyl, isoindolyl, isoquinolinyl,isothiazolyl, isothiazolopyridinyl, isoxazolyl, isoxazolopyridinyl,methylenedioxyphenyl, morpholinyl, naphthyridinyl,octahydroisoquinolinyl, oxadiazolyl, 1,2,3-oxadiazolyl,1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, oxazolidinyl,oxazolyl, oxazolopyridinyl, oxazolidinylperimidinyl, oxindolyl,pyrimidinyl, phenanthridinyl, phenanthrolinyl, phenazinyl,phenothiazinyl, phenoxathiinyl, phenoxazinyl, phthalazinyl, piperazinyl,piperidinyl, piperidonyl, 4-piperidonyl, piperonyl, pteridinyl, purinyl,pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolopyridinyl,pyrazolyl, pyridazinyl, pyridooxazolyl, pyridoimidazolyl,pyridothiazolyl, pyridinyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl,2-pyrrolidonyl, 2H-pyrrolyl, pyrrolyl, quinolinyl, 4H-quinolizinyl,quinoxalinyl, quinuclidinyl, tetrazolyl, tetrahydrofuranyl,tetrahydroisoquinolinyl, tetrahydroquinolinyl, 6H-1,2,5-thiadiazinyl,1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl,1,3,4-thiadiazolyl, thianthrenyl, thiazolyl, thienyl, thiazolopyridinyl,thienothiazolyl, thienooxazolyl, thienoimidazolyl, thiophenyl,triazinyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl,1,3,4-triazolyl, and xanthenyl. Also included are fused ring and spirocompounds containing, for example, the above heterocycles.

Examples of 5- to 10-membered heterocycles include, but are not limitedto, pyridinyl, furanyl, thienyl, pyrrolyl, pyrazolyl, pyrazinyl,piperazinyl, piperidinyl, imidazolyl, imidazolidinyl, indolyl,tetrazolyl, isoxazolyl, morpholinyl, oxazolyl, oxadiazolyl,oxazolidinyl, tetrahydrofuranyl, thiadiazinyl, thiadiazolyl, thiazolyl,triazinyl, triazolyl, benzimidazolyl, 1H-indazolyl, benzofuranyl,benzothiofuranyl, benztetrazolyl, benzotriazolyl, benzisoxazolyl,benzoxazolyl, oxindolyl, benzoxazolinyl, benzthiazolyl,benzisothiazolyl, isatinoyl, isoquinolinyl, octahydroisoquinolinyl,tetrahydroisoquinolinyl, tetrahydroquinolinyl, isoxazolopyridinyl,quinazolinyl, quinolinyl, isothiazolopyridinyl, thiazolopyridinyl,oxazolopyridinyl, imidazolopyridinyl, and pyrazolopyridinyl.

Examples of 5- to 6-membered heterocycles include, but are not limitedto, pyridinyl, furanyl, thienyl, pyrrolyl, pyrazolyl, pyrazinyl,piperazinyl, piperidinyl, imidazolyl, imidazolidinyl, indolyl,tetrazolyl, isoxazolyl, morpholinyl, oxazolyl, oxadiazolyl,oxazolidinyl, tetrahydrofuranyl, thiadiazinyl, thiadiazolyl, thiazolyl,triazinyl, and triazolyl. Also included are fused ring and spirocompounds containing, for example, the above heterocycles.

As used herein, the term “bicyclic heterocycle” or “bicyclicheterocyclic group” is intended to mean a stable 9- or 10-memberedheterocyclic ring system which contains two fused rings and consists ofcarbon atoms and 1, 2, 3, or 4 heteroatoms independently selected fromthe group consisting of N, O and S. Of the two fused rings, one ring isa 5- or 6-membered monocyclic aromatic ring comprising a 5-memberedheteroaryl ring, a 6-membered heteroaryl ring or a benzo ring, eachfused to a second ring. The second ring is a 5- or 6-membered monocyclicring which is saturated, partially unsaturated, or unsaturated, andcomprises a 5-membered heterocycle, a 6-membered heterocycle or acarbocycle (provided the first ring is not benzo when the second ring isa carbocycle).

The bicyclic heterocyclic group may be attached to its pendant group atany heteroatom or carbon atom which results in a stable structure. Thebicyclic heterocyclic group described herein may be substituted oncarbon or on a nitrogen atom if the resulting compound is stable. It ispreferred that when the total number of S and O atoms in the heterocycleexceeds 1, then these heteroatoms are not adjacent to one another. It ispreferred that the total number of S and O atoms in the heterocycle isnot more than 1.

Examples of a bicyclic heterocyclic group are, but not limited to,quinolinyl, isoquinolinyl, phthalazinyl, quinazolinyl, indolyl,isoindolyl, indolinyl, 1H-indazolyl, benzimidazolyl,1,2,3,4-tetrahydroquinolinyl, 1,2,3,4-tetrahydroisoquinolinyl,5,6,7,8-tetrahydro-quinolinyl, 2,3-dihydro-benzofuranyl, chromanyl,1,2,3,4-tetrahydro-quinoxalinyl, and 1,2,3,4-tetrahydro-quinazolinyl.

As used herein, the term “aromatic heterocyclic group” or “heteroaryl”is intended to mean stable monocyclic and polycyclic aromatichydrocarbons that include at least one heteroatom ring member such assulfur, oxygen, or nitrogen. Heteroaryl groups include, withoutlimitation, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl,furyl, quinolyl, isoquinolyl, thienyl, imidazolyl, thiazolyl, indolyl,pyrroyl, oxazolyl, benzofuryl, benzothienyl, benzthiazolyl, isoxazolyl,pyrazolyl, triazolyl, tetrazolyl, indazolyl, 1,2,4-thiadiazolyl,isothiazolyl, purinyl, carbazolyl, benzimidazolyl, benzodioxolanyl, andbenzodioxane. Heteroaryl groups are substituted or unsubstituted. Thenitrogen atom is substituted or unsubstituted (i.e., N or NR wherein Ris H or another substituent, if defined). The nitrogen and sulfurheteroatoms may optionally be oxidized (i.e., N→O and S(O)_(p), whereinp is 0, 1 or 2).

Examples of 5- to 6-membered heteroaryls include, but are not limitedto, pyridinyl, furanyl, thienyl, pyrrolyl, pyrazolyl, pyrazinyl,imidazolyl, imidazolidinyl, tetrazolyl, isoxazolyl, oxazolyl,oxadiazolyl, oxazolidinyl, thiadiazinyl, thiadiazolyl, thiazolyl,triazinyl, and triazolyl.

Bridged rings are also included in the definition of heterocycle. Abridged ring occurs when one or more, preferably one to three, atoms(i.e., C, O, N, or S) link two non-adjacent carbon or nitrogen atoms.Examples of bridged rings include, but are not limited to, one carbonatom, two carbon atoms, one nitrogen atom, two nitrogen atoms, and acarbon-nitrogen group. It is noted that a bridge always converts amonocyclic ring into a tricyclic ring. When a ring is bridged, thesubstituents recited for the ring may also be present on the bridge.

The term “counter ion” is used to represent a negatively charged speciessuch as chloride, bromide, hydroxide, acetate, and sulfate or apositively charged species such as sodium (Na+), potassium (K+),ammonium (R_(n)NH_(m)+ where n=0-4 and m=0-4) and the like.

When a dotted ring is used within a ring structure, this indicates thatthe ring structure may be saturated, partially saturated or unsaturated.

As used herein, the term “amine protecting group” means any group knownin the art of organic synthesis for the protection of amine groups whichis stable to an ester reducing agent, a disubstituted hydrazine, R4-Mand R7-M, a nucleophile, a hydrazine reducing agent, an activator, astrong base, a hindered amine base and a cyclizing agent. Such amineprotecting groups fitting these criteria include those listed in Wuts,P. G. M. et al., Protecting Groups in Organic Synthesis, 4th Edition,Wiley (2007) and The Peptides: Analysis, Synthesis, Biology, Vol. 3,Academic Press, New York (1981), the disclosure of which is herebyincorporated by reference. Examples of amine protecting groups include,but are not limited to, the following: (1) acyl types such as formyl,trifluoroacetyl, phthalyl, and p-toluenesulfonyl; (2) aromatic carbamatetypes such as benzyloxycarbonyl (Cbz) and substitutedbenzyloxycarbonyls, 1-(p-biphenyl)-1-methylethoxycarbonyl, and9-fluorenylmethyloxycarbonyl (Fmoc); (3) aliphatic carbamate types suchas tert-butyloxycarbonyl (Boc), ethoxycarbonyl,diisopropylmethoxycarbonyl, and allyloxycarbonyl; (4) cyclic alkylcarbamate types such as cyclopentyloxycarbonyl and adamantyloxycarbonyl;(5) alkyl types such as triphenylmethyl and benzyl; (6) trialkylsilanesuch as trimethylsilane; (7) thiol containing types such asphenylthiocarbonyl and dithiasuccinoyl; and (8) alkyl types such astriphenylmethyl, methyl, and benzyl; and substituted alkyl types such as2,2,2-trichloroethyl, 2-phenylethyl, and t-butyl; and trialkylsilanetypes such as trimethylsilane.

As referred to herein, the term “substituted” means that at least onehydrogen atom is replaced with a non-hydrogen group, provided thatnormal valencies are maintained and that the substitution results in astable compound. Ring double bonds, as used herein, are double bondsthat are formed between two adjacent ring atoms (e.g., C═C, C═N, orN═N).

In cases wherein there are nitrogen atoms (e.g., amines) on compounds ofthe present invention, these may be converted to N-oxides by treatmentwith an oxidizing agent (e.g., mCPBA and/or hydrogen peroxides) toafford other compounds of this invention. Thus, shown and claimednitrogen atoms are considered to cover both the shown nitrogen and itsN-oxide (N→O) derivative.

When any variable occurs more than one time in any constituent orformula for a compound, its definition at each occurrence is independentof its definition at every other occurrence. Thus, for example, if agroup is shown to be substituted with 0-3 R, then said group mayoptionally be substituted with up to three R groups, and at eachoccurrence R is selected independently from the definition of R.

When a bond to a substituent is shown to cross a bond connecting twoatoms in a ring, then such substituent may be bonded to any atom on thering. When a substituent is listed without indicating the atom in whichsuch substituent is bonded to the rest of the compound of a givenformula, then such substituent may be bonded via any atom in suchsubstituent.

Combinations of substituents and/or variables are permissible only ifsuch combinations result in stable compounds.

The phrase “pharmaceutically acceptable” is employed herein to refer tothose compounds, materials, compositions, and/or dosage forms that are,within the scope of sound medical judgment, suitable for use in contactwith the tissues of human beings and animals without excessive toxicity,irritation, allergic response, and/or other problem or complication,commensurate with a reasonable benefit/risk ratio.

As used herein, “pharmaceutically acceptable salts” refer to derivativesof the disclosed compounds wherein the parent compound is modified bymaking acid or base salts thereof. Examples of pharmaceuticallyacceptable salts include, but are not limited to, mineral or organicacid salts of basic groups such as amines; and alkali or organic saltsof acidic groups such as carboxylic acids. The pharmaceuticallyacceptable salts include the conventional non-toxic salts or thequaternary ammonium salts of the parent compound formed, for example,from non-toxic inorganic or organic acids. For example, suchconventional non-toxic salts include those derived from inorganic acidssuch as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, andnitric; and the salts prepared from organic acids such as acetic,propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric,ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic,benzoic, salicylic, sulfanilic, 2-acetoxybenzoic, fumaric,toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, andisethionic, and the like.

The pharmaceutically acceptable salts of the present invention can besynthesized from the parent compound that contains a basic or acidicmoiety by conventional chemical methods. Generally, such salts can beprepared by reacting the free acid or base forms of these compounds witha stoichiometric amount of the appropriate base or acid in water or inan organic solvent, or in a mixture of the two; generally, nonaqueousmedia like ether, ethyl acetate, ethanol, isopropanol, or acetonitrileare preferred. Lists of suitable salts are found in Allen, Jr., L. V.,ed., Remington: The Science and Practice of Pharmacy, 22nd Edition,Pharmaceutical Press, London, UK (2012), the disclosure of which ishereby incorporated by reference.

In addition, compounds of formula I may have prodrug forms. Any compoundthat will be converted in vivo to provide the bioactive agent (i.e., acompound of formula I) is a prodrug within the scope and spirit of theinvention. Various forms of prodrugs are well known in the art. Forexamples of such prodrug derivatives, see:

a) Bundgaard, H., ed., Design of Prodrugs, Elsevier (1985), and Widder,K. et al., eds., Methods in Enzymology, 112:309-396, Academic Press(1985);

b) Bundgaard, H., Chapter 5, “Design and Application of Prodrugs”,Krosgaard-Larsen, P. et al., eds., A Textbook of Drug Design andDevelopment, pp. 113-191, Harwood Academic Publishers (1991);

c) Bundgaard, H., Adv. Drug Deliv. Rev., 8:1-38 (1992);

d) Bundgaard, H. et al., J. Pharm. Sci., 77:285 (1988);

e) Kakeya, N. et al., Chem. Pharm. Bull., 32:692 (1984); and

f) Rautio, J., ed., Prodrugs and Targeted Delivery (Methods andPrinciples in Medicinal Chemistry), Vol. 47, Wiley-VCH (2011).

Compounds containing a carboxy group can form physiologicallyhydrolyzable esters that serve as prodrugs by being hydrolyzed in thebody to yield formula I compounds per se. Such prodrugs are preferablyadministered orally since hydrolysis in many instances occursprincipally under the influence of the digestive enzymes. Parenteraladministration may be used where the ester per se is active, or in thoseinstances where hydrolysis occurs in the blood. Examples ofphysiologically hydrolyzable esters of compounds of formula I includeC₁₋₆alkyl, C₁₋₆alkylbenzyl, 4-methoxybenzyl, indanyl, phthalyl,methoxymethyl, C₁₋₆ alkanoyloxy-C₁₋₆alkyl (e.g., acetoxymethyl,pivaloyloxymethyl or propionyloxymethyl),C₁₋₆alkoxycarbonyloxy-C₁₋₆alkyl (e.g., methoxycarbonyl-oxymethyl orethoxycarbonyloxymethyl, glycyloxymethyl, phenylglycyloxymethyl,(5-methyl-2-oxo-1,3-dioxolen-4-yl)-methyl), and other well knownphysiologically hydrolyzable esters used, for example, in the penicillinand cephalosporin arts. Such esters may be prepared by conventionaltechniques known in the art.

Preparation of prodrugs is well known in the art and described in, forexample, King, F. D., ed., Medicinal Chemistry: Principles and Practice,The Royal Society of Chemistry, Cambridge, UK (2nd Edition, reproduced(2006)); Testa, B. et al., Hydrolysis in Drug and Prodrug Metabolism.Chemistry, Biochemistry and Enzymology, VCHA and Wiley-VCH, Zurich,Switzerland (2003); Wermuth, C. G., ed., The Practice of MedicinalChemistry, 3rd Edition, Academic Press, San Diego, Calif. (2008).

The present invention is intended to include all isotopes of atomsoccurring in the present compounds. Isotopes include those atoms havingthe same atomic number but different mass numbers. By way of generalexample and without limitation, isotopes of hydrogen include deuteriumand tritium. Isotopes of carbon include ¹³C and ¹⁴C.Isotopically-labeled compounds of the invention can generally beprepared by conventional techniques known to those skilled in the art orby processes analogous to those described herein, using an appropriateisotopically-labeled reagent in place of the non-labeled reagentotherwise employed.

The term “solvate” means a physical association of a compound of thisinvention with one or more solvent molecules, whether organic orinorganic. This physical association includes hydrogen bonding. Incertain instances the solvate will be capable of isolation, for examplewhen one or more solvent molecules are incorporated in the crystallattice of the crystalline solid. The solvent molecules in the solvatemay be present in a regular arrangement and/or a non-orderedarrangement. The solvate may comprise either a stoichiometric ornonstoichiometric amount of the solvent molecules. “Solvate” encompassesboth solution-phase and isolable solvates. Exemplary solvates include,but are not limited to, hydrates, ethanolates, methanolates, andisopropanolates. Methods of solvation are generally known in the art.

Abbreviations as used herein, are defined as follows: “1×” for once,“2×” for twice, “3×” for thrice, “° C.” for degrees Celsius, “eq” forequivalent or equivalents, “g” for gram or grams, “mg” for milligram ormilligrams, “L” for liter or liters, “mL” for milliliter or milliliters,“μL” for microliter or microliters, “N” for normal, “M” for molar,“mmol” for millimole or millimoles, “min” for minute or min, “h” forhour or h, “rt” for room temperature, “RT” for retention time, “atm” foratmosphere, “psi” for pounds per square inch, “conc.” for concentrate,“aq” for “aqueous”, “sat” or “sat'd” for saturated, “MW” for molecularweight, “mp” for melting point, “MS” or “Mass Spec” for massspectrometry, “ESI” for electrospray ionization mass spectroscopy, “HR”for high resolution, “HRMS” for high resolution mass spectrometry,“LCMS” for liquid chromatography mass spectrometry, “HPLC” for highpressure liquid chromatography, “RP HPLC” for reverse phase HPLC, “TLC”or “tlc” for thin layer chromatography, “NMR” for nuclear magneticresonance spectroscopy, “nOe” for nuclear Overhauser effectspectroscopy, “¹H” for proton, “δ” for delta, “s” for singlet, “d” fordoublet, “t” for triplet, “q” for quartet, “m” for multiplet, “br” forbroad, “Hz” for hertz, and “α”, “β”, “R”, “S”, “E”, “Z” and “ee” arestereochemical designations familiar to one skilled in the art.

-   AcOH or HOAc acetic acid-   CAN acetonitrile-   Alk alkyl-   BBr₃ boron tribromide-   Bn benzyl-   Boc tert-butyloxycarbonyl-   BOP reagent benzotriazol-1-yloxytris(dimethylamino)phosphonium    hexafluorophosphate-   Bu butyl-   i-Bu isobutyl-   t-Bu tert-butyl-   t-BuOH tert-butanol-   Cbz carbobenzyloxy-   CDCl₃ deutero-chloroform-   CD₃OD deutero-methanol-   CDI 1,1′-carbonyldiimidazole-   CH₂Cl₂ dichloromethane-   CH₃CN acetonitrile-   CHCl₃ chloroform-   CO₂ carbon dioxide-   DCM dichloromethane-   DIEA, DIPEA or diisopropylethylamine-   Hunig's base-   DMF dimethyl formamide-   DMSO dimethyl sulfoxide-   EDC 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide-   Et ethyl-   Et₃N or TEA triethylamine-   Et₂O diethyl ether-   EtOAc ethyl acetate-   EtOH ethanol-   HCl hydrochloric acid-   HPLC high-performance liquid chromatography-   K₂CO₃ potassium carbonate-   K₂HPO₄ potassium hydrogenphosphate-   LCMS liquid chromatography mass spectrometry-   LiHMDS lithium bis(trimethylsilyl)amide-   LG leaving group-   Me methyl-   MeOH methanol-   MgSO₄ magnesium sulfate-   MsOH or MSA methylsulfonic acid-   NaCl sodium chloride-   Na₂CO₃ sodium carbonate-   NaHCO₃ sodium bicarbonate-   NaOH sodium hydroxide-   Na₂SO₄ sodium sulfate-   NH₃ ammonia-   NH₃Cl ammonium chloride-   NH₄OAc ammonium acetate-   Pd(OAc)₂ palladium(II) acetate-   Pd(PPh₃)₄ tetrakis(triphenylphosphine)palladium(0)-   PG protecting group-   Ph phenyl-   Pr propyl-   i-Pr isopropyl-   i-PrOH or IPA isopropanol-   Rt retention time-   SiO₂ silica oxide-   SFC supercritical fluid chromatography-   TEA triethylamine-   TFA trifluoroacetic acid-   THF tetrahydrofuran-   TiCl₄ titanium tetrachloride-   T3P® 1-propanephosphonic acid cyclic anhydride

Synthesis

The compounds of Formula (I) may be prepared by the exemplary processesdescribed in the following schemes and working examples, as well asrelevant published literature procedures that are used by one skilled inthe art. Exemplary reagents and procedures for these reactions appearhereinafter and in the working examples.

Protection and de-protection in the processes below may be carried outby procedures generally known in the art (see, for example, Wuts, P. G.M. et al., Protecting Groups in Organic Synthesis, 4th Edition, Wiley(2007)). General methods of organic synthesis and functional grouptransformations are found in: Trost, B. M. et al., eds., ComprehensiveOrganic Synthesis: Selectivity, Strategy & Efficiency in Modern OrganicChemistry, Pergamon Press, New York, N.Y. (1991); Smith, M. B. et al.,March's Advanced Organic Chemistry: Reactions, Mechanisms, andStructure. 6th Edition, Wiley & Sons, New York, N.Y. (2007); Katritzky,A. R. et al, eds., Comprehensive Organic Functional GroupsTransformations II, 2nd Edition, Elsevier Science Inc., Tarrytown, N.Y.(2004); Larock, R. C., Comprehensive Organic Transformations, VCHPublishers, Inc., New York, N.Y. (1999), and references therein.

Preferred methods include, but are not limited to, those describedbelow. All references cited herein are hereby incorporated in theirentirety herein by reference.

The novel compounds of this invention may be prepared using thereactions and techniques described in this section. Also, in thedescription of the synthetic methods described below, it is to beunderstood that all proposed reaction conditions, including choice ofsolvent, reaction atmosphere, reaction temperature, duration of theexperiment and workup procedures, are chosen to be the conditionsstandard for that reaction, which should be readily recognized by oneskilled in the art. Restrictions to the substituents that are compatiblewith the reaction conditions will be readily apparent to one skilled inthe art and alternate methods must then be used.

It will also be recognized that another major consideration in theplanning of any synthetic route in this field is the judicious choice ofthe protecting group used for protection of the reactive functionalgroups present in the compounds described in this invention. Anauthoritative account describing the many alternatives to the trainedpractitioner is Greene et al. (Protective Groups in Organic Synthesis,Wiley and Sons (1991)).

Initial condensation of bromoketoester A with amine B yieldsintermediate C. Alternatively, compound C can be prepared by thealkylation of amine B with bromoacetate D followed by condensation ofintermediate E with acid chloride F. Intermediate C can be converted tothe amine intermediate G. Acylation with acid chloride L followed bycyclization yields sulfone compounds of general structure M.Alternatively, condensation of G with compound H yields compound I aftercyclization. Amide formation with J yields compounds of the generalstructure K.

IV. BIOLOGY

APJ receptor was discovered in 1993 as an orphan G protein-coupledreceptor (GPCR) and was subsequently found to recognize apelin peptideas its endogenous ligand. It belongs to class A of GPCRs and has aclassical 7-transmembrane domain structure, exhibiting greatest sequencehomology to angiotensin AT1 receptor (for review see Pitkin, S. L. etal., Pharmacol. Rev., 62(3):331-342 (2010)). APJ is expressed in widevariety of peripheral tissues and the CNS, and has relatively highexpression in placenta, myocardium, vascular endothelial cells, smoothmuscle cells as well as cardiac myocytes (Kleinz, J. M. et al.,Pharmacol. Ther., 107(2):198-211 (2005)). Apelin peptide was originallyidentified in bovine stomach extract and remains to date the only knownendogenous ligand and agonist of APJ receptor (Tatemoto, K. et al.,Biochem. Biophys. Res. Commun., 255:471-476 (1998)). Tissue expressionof apelin gene mirrors closely the APJ expression pattern and has beenpostulated to act in an autocrine or paracrine manner, often exemplifiedby reference to “apelin-APJ system”. Apelin gene encodes 77 amino acidprecursor peptide that is cleaved to form mature secreted peptideundergoing further proteolytic cleavage forming shorter C-terminalfragments. Apelin-36, -17 and -13 represent the major active forms withthe pyroglutamated form of apelin-13 being the most stable and the mostabundant form present in the cardiac tissue (Maguire, J. J. et al.,Hypertension, 54(3):598-604 (2009)). Apelin has very short half life incirculation, estimated to be less than 5 minutes (Japp, A. G. et al.,Circulation, 121(16):1818-1827 (2010)).

Activation of APJ receptor is known to inhibit forskolin-stimulatedcyclic AMP (cAMP) levels in pertussis toxin-sensitive manner, indicatingcoupling to the Gi proteins. The binding affinity of apelin and the EC₅₀values in the cAMP assay are reported to be in the sub-nanomolar range(for review see Pitkin, S. L. et al., Pharmacol. Rev., 62(3):331-342(2010)). In addition to cAMP inhibition, APJ receptor activation alsoleads to β-arrestin recruitment, receptor internalization and activationof extracellular-regulated kinases (ERKs) (for review see Kleinz, J. M.et al., Pharmacol. Ther., 107(2):198-211 (2005)). Which of thesesignaling mechanisms contribute to modulation of downstreamphysiological effects of apelin is not clear at present. APJ receptorhas been shown to interact with the AT1 receptor. While apelin does notbind AT1 and angiotensin II does not bind APJ, it has been postulatedthat certain physiological actions of apelin are mediated, at least inpart, via functional antagonism of the angiotensin II and AT1 receptorpathway (Chun, A. J. et al., J. Clin. Invest., 118(10):3343-3354(2008)).

It is also desirable and preferable to find compounds with advantageousand improved characteristics compared with known HF treatment agents, inone or more of the following categories that are given as examples, andare not intended to be limiting: (a) pharmacokinetic properties,including oral bioavailability, half life, and clearance; (b)pharmaceutical properties; (c) dosage requirements; (d) factors thatdecrease blood drug concentration peak-to-trough characteristics; (e)factors that increase the concentration of active drug at the receptor;(f) factors that decrease the liability for clinical drug-druginteractions; (g) factors that decrease the potential for adverseside-effects, including selectivity versus other biological targets; and(h) improved therapeutic index.

As used herein, the term “patient” encompasses all mammalian species.

As used herein, the term “subject” refers to any human or non-humanorganism that could potentially benefit from treatment with an APJagonist. Exemplary subjects include human beings of any age with riskfactors for development of heart failure and the sequelae thereof,angina, ischemia, cardiac ischemia, myocardial infarction, reperfusioninjury, angioplastic restenosis, hypertension, vascular complications ofdiabetes, obesity or endotoxemia, stroke, as well as atherosclerosis,coronary artery disease, acute coronary syndrome, and/or dyslipidemias.

As used herein, “treating” or “treatment” cover the treatment of adisease-state in a mammal, particularly in a human, and include: (a)inhibiting the disease-state, i.e., arresting it development; and/or (b)relieving the disease-state, i.e., causing regression of the diseasestate.

As used herein, “prophylaxis” or “prevention” cover the preventivetreatment of a subclinical disease-state in a mammal, particularly in ahuman, aimed at reducing the probability of the occurrence of a clinicaldisease-state. Patients are selected for preventative therapy based onfactors that are known to increase risk of suffering a clinical diseasestate compared to the general population. “Prophylaxis” therapies can bedivided into (a) primary prevention and (b) secondary prevention.Primary prevention is defined as treatment in a subject that has not yetpresented with a clinical disease state, whereas secondary prevention isdefined as preventing a second occurrence of the same or similarclinical disease state.

As used herein, “risk reduction” covers therapies that lower theincidence of development of a clinical disease state. As such, primaryand secondary prevention therapies are examples of risk reduction.

“Therapeutically effective amount” is intended to include an amount of acompound of the present invention that is effective when administeredalone or in combination to modulate APJ and/or to prevent or treat thedisorders listed herein. When applied to a combination, the term refersto combined amounts of the active ingredients that result in thepreventive or therapeutic effect, whether administered in combination,serially, or simultaneously.

Intracellular cAMP Accumulation Assay

HEK293 cells stably expressing human APJ receptor were used to assessthe activity of compounds. Cultured cells were detached and resuspendedin the cAMP Homogeneous Time-Resolved Fluorescence (HTRF) assay buffer(Cisbio cat; #62AM4PEJ). The assay was performed in 384-well assayplates (Perkin-Elmer; cat #6008289) according to assay protocol providedby the manufacturer. Serial dilutions of a compound together with assaybuffer containing 0.2 nM IBMX and 2 μM forskolin were added to each wellcontaining 5,000 cells and incubated for 30 minutes at room temperature.Subsequently, cAMP D2 reagent was added in the lysis buffer followed bythe EuK antibody (Cisbio; cat #62AM4PEJ) and incubated for 60 min. Thefluorescence emission ratio was measured using fluorometer. Theintracellular cAMP concentrations (compound-stimulated inhibition offorskolin-mediated cAMP production) were calculated by extrapolationfrom a standard curve using known cAMP concentrations. The EC₅₀ valueswere obtained by fitting the data to a sigmoidal concentration-responsecurve with variable slope. The maximal achievable inhibition offorskolin-induced cAMP levels (Y_(max)) for each compound was expressedas relative percentage of inhibition attained using pyroglutamatedapelin-13 ((Pyr1)apelin-13) peptide, which was set to 100%.

The examples disclosed below were tested in the APJ in vitro assaysdescribed above and were found having human APJ cyclic AMP (hcAMP)activity. The EC₅₀ value of each compound is presented at the end of theexample description.

The compounds of the present invention possess activity as agonists ofAPJ receptor, and, therefore, may be used in the treatment of diseasesassociated with APJ activity. Accordingly, the compounds of the presentinvention can be administered to mammals, preferably humans, for thetreatment of a variety of conditions and disorders, including, but notlimited to, treating, preventing, or slowing the progression of heartfailure, coronary artery disease, peripheral vascular disease,atherosclerosis, diabetes, metabolic syndrome and the sequelae ofthereof, hypertension, pulmonary hypertension, cerebrovasculardisorders, atrial fibrillation, angina, ischemia, stroke, myocardialinfarction, acute coronary syndrome, reperfusion injury, angioplasticrestenosis, vascular complications of diabetes and obesity.

The biological activity of the exemplified compounds of this inventiondetermined by the assay described above is shown at the end of eachexample. The APJ cAMP EC₅₀ potency ranges are as follows: A=0.01-10 nM;B=10.01-100 nM; C=100.01-300 nM.

V. PHARMACEUTICAL COMPOSITIONS, FORMULATIONS AND COMBINATIONS

The compounds of this invention can be administered for any of the usesdescribed herein by any suitable means, for example, orally, such astablets, capsules (each of which includes sustained release or timedrelease formulations), pills, powders, granules, elixirs, tinctures,suspensions (including nanosuspensions, microsuspensions, spray-drieddispersions), syrups, and emulsions; sublingually; bucally;parenterally, such as by subcutaneous, intravenous, intramuscular, orintrasternal injection, or infusion techniques (e.g., as sterileinjectable aqueous or non-aqueous solutions or suspensions); nasally,including administration to the nasal membranes, such as by inhalationspray; topically, such as in the form of a cream or ointment; orrectally such as in the form of suppositories. They can be administeredalone, but generally will be administered with a pharmaceutical carrierselected on the basis of the chosen route of administration and standardpharmaceutical practice.

The term “pharmaceutical composition” means a composition comprising acompound of the invention in combination with at least one additionalpharmaceutically acceptable carrier. A “pharmaceutically acceptablecarrier” refers to media generally accepted in the art for the deliveryof biologically active agents to animals, in particular, mammals,including, i.e., adjuvant, excipient or vehicle, such as diluents,preserving agents, fillers, flow regulating agents, disintegratingagents, wetting agents, emulsifying agents, suspending agents,sweetening agents, flavoring agents, perfuming agents, antibacterialagents, antifungal agents, lubricating agents and dispensing agents,depending on the nature of the mode of administration and dosage forms.

Pharmaceutically acceptable carriers are formulated according to anumber of factors well within the purview of those of ordinary skill inthe art. These include, without limitation: the type and nature of theactive agent being formulated; the subject to which the agent-containingcomposition is to be administered; the intended route of administrationof the composition; and the therapeutic indication being targeted.Pharmaceutically acceptable carriers include both aqueous andnon-aqueous liquid media, as well as a variety of solid and semi-soliddosage forms. Such carriers can include a number of differentingredients and additives in addition to the active agent, suchadditional ingredients being included in the formulation for a varietyof reasons, e.g., stabilization of the active agent, binders, etc., wellknown to those of ordinary skill in the art. Descriptions of suitablepharmaceutically acceptable carriers, and factors involved in theirselection, are found in a variety of readily available sources such as,for example, Allen, Jr., L. V. et al., Remington: The Science andPractice of Pharmacy (2 Volumes), 22nd Edition, Pharmaceutical Press(2012),

The dosage regimen for the compounds of the present invention will, ofcourse, vary depending upon known factors, such as the pharmacodynamiccharacteristics of the particular agent and its mode and route ofadministration; the species, age, sex, health, medical condition, andweight of the recipient; the nature and extent of the symptoms; the kindof concurrent treatment; the frequency of treatment; the route ofadministration, the renal and hepatic function of the patient, and theeffect desired.

By way of general guidance, the daily oral dosage of each activeingredient, when used for the indicated effects, will range betweenabout 0.001 to about 5000 mg per day, preferably between about 0.01 toabout 1000 mg per day, and most preferably between about 0.1 to about250 mg per day. Intravenously, the most preferred doses will range fromabout 0.01 to about 10 mg/kg/minute during a constant rate infusion.Compounds of this invention may be administered in a single daily dose,or the total daily dosage may be administered in divided doses of two,three, or four times daily.

The compounds are typically administered in admixture with suitablepharmaceutical diluents, excipients, or carriers (collectively referredto herein as pharmaceutical carriers) suitably selected with respect tothe intended form of administration, e.g., oral tablets, capsules,elixirs, and syrups, and consistent with conventional pharmaceuticalpractices.

Dosage forms (pharmaceutical compositions) suitable for administrationmay contain from about 1 milligram to about 2000 milligrams of activeingredient per dosage unit. In these pharmaceutical compositions theactive ingredient will ordinarily be present in an amount of about0.1-95% by weight based on the total weight of the composition.

A typical capsule for oral administration contains at least one of thecompounds of the present invention (250 mg), lactose (75 mg), andmagnesium stearate (15 mg). The mixture is passed through a 60 meshsieve and packed into a No. 1 gelatin capsule.

A typical injectable preparation is produced by aseptically placing atleast one of the compounds of the present invention (250 mg) into avial, aseptically freeze-drying and sealing. For use, the contents ofthe vial are mixed with 2 mL of physiological saline, to produce aninjectable preparation.

The present invention includes within its scope pharmaceuticalcompositions comprising, as an active ingredient, a therapeuticallyeffective amount of at least one of the compounds of the presentinvention, alone or in combination with a pharmaceutical carrier.Optionally, compounds of the present invention can be used alone, incombination with other compounds of the invention, or in combinationwith one or more other therapeutic agent(s), e.g., agents used intreatment of heart failure or other pharmaceutically active material.

The compounds of the present invention may be employed in combinationwith other APJ agonists or one or more other suitable therapeutic agentsuseful in the treatment of the aforementioned disorders including:agents for treating heart failure, anti-hypertensive agents,anti-atherosclerotic agents, anti-dyslipidemic agents, anti-diabeticagents, anti-hyperglycemic agents, anti-hyperinsulinemic agents,anti-thrombotic agents, anti-retinopathic agents, anti-neuropathicagents, anti-nephropathic agents, anti-ischemic agents, anti-obesityagents, anti-hyperlipidemic agents, anti-hypertriglyceridemic agents,anti-hypercholesterolemic agents, anti-restenotic agents,anti-pancreatic agents, lipid lowering agents, anorectic agents, memoryenhancing agents, anti-dementia agents, cognition promoting agents,appetite suppressants, and agents for treating peripheral arterialdisease.

The compounds of the present invention may be employed in combinationwith additional therapeutic agent(s) selected from one or more,preferably one to three, of the following therapeutic agents in treatingheart failure and coronary artery disease: ACE inhibitors, β-blockers,diuretics, mineralocorticoid receptor antagonists, renin inhibitors,calcium channel blockers, angiotensin II receptor antagonists, nitrates,digitalis compounds, inotropic agents and β-receptor agonists,anti-hyperlipidemic agents, plasma HDL-raising agents,anti-hypercholesterolemic agents, cholesterol biosynthesis inhibitors(such as HMG CoA reductase inhibitors), LXR agonist, probucol,raloxifene, nicotinic acid, niacinamide, cholesterol absorptioninhibitors, bile acid sequestrants (such as anion exchange resins, orquaternary amines (e.g., cholestyramine or colestipol), low densitylipoprotein receptor inducers, clofibrate, fenofibrate, benzofibrate,cipofibrate, gemfibrizol, vitamin B₆, vitamin B₁₂, anti-oxidantvitamins, anti-diabetes agents, platelet aggregation inhibitors,fibrinogen receptor antagonists, aspirin and fibric acid derivatives.

The compounds of the invention may be used in combination with one ormore, preferably one to three, of the following anti-diabetic agentsdepending on the desired target therapy. Studies indicate that diabetesand hyperlipidemia modulation can be further improved by the addition ofa second agent to the therapeutic regimen. Examples of anti-diabeticagents include, but are not limited to, sulfonylureas (such aschlorpropamide, tolbutamide, acetohexamide, tolazamide, glyburide,gliclazide, glynase, glimepiride, and glipizide), biguanides (such asmetformin), thiazolidinediones (such as ciglitazone, pioglitazone,troglitazone, and rosiglitazone), and related insulin sensitizers, suchas selective and non-selective activators of PPARα, PPARβ and PPARγ;dehydroepiandrosterone (also referred to as DHEA or its conjugatedsulphate ester, DHEA-SO₄); anti-glucocorticoids; TNFα inhibitors;dipeptidyl peptidase IV (DPP4) inhibitor (such as sitagliptin,saxagliptin), GLP-1 agonists or analogs (such as exenatide),α-glucosidase inhibitors (such as acarbose, miglitol, and voglibose),pramlintide (a synthetic analog of the human hormone amylin), otherinsulin secretagogues (such as repaglinide, gliquidone, andnateglinide), insulin, as well as the therapeutic agents discussed abovefor treating heart failure and atherosclerosis.

The compounds of the invention may be used in combination with one ormore, preferably one to three, of the following anti-obesity agentsselected from phenylpropanolamine, phentermine, diethylpropion,mazindol, fenfluramine, dexfenfluramine, phentiramine, β₃-adrenergicreceptor agonist agents; sibutramine, gastrointestinal lipase inhibitors(such as orlistat), and leptins. Other agents used in treating obesityor obesity-related disorders include neuropeptide Y, enterostatin,cholecytokinin, bombesin, amylin, histamine H₃ receptors, dopamine D₂receptor modulators, melanocyte stimulating hormone, corticotrophinreleasing factor, galanin and gamma amino butyric acid (GABA).

The above other therapeutic agents, when employed in combination withthe compounds of the present invention may be used, for example, inthose amounts indicated in the Physicians' Desk Reference, as in thepatents set out above, or as otherwise determined by one of ordinaryskill in the art.

Particularly when provided as a single dosage unit, the potential existsfor a chemical interaction between the combined active ingredients. Forthis reason, when the compound of the present invention and a secondtherapeutic agent are combined in a single dosage unit they areformulated such that although the active ingredients are combined in asingle dosage unit, the physical contact between the active ingredientsis minimized (that is, reduced). For example, one active ingredient maybe enteric coated. By enteric coating one of the active ingredients, itis possible not only to minimize the contact between the combined activeingredients but also to control the release of one of these componentsin the gastrointestinal tract such that one of these components is notreleased in the stomach but rather is released in the intestines. One ofthe active ingredients may also be coated with a material that affects asustained-release throughout the gastrointestinal tract and also servesto minimize physical contact between the combined active ingredients.Furthermore, the sustained-released component can be additionallyenteric coated such that the release of this component occurs only inthe intestine. Still another approach would involve the formulation of acombination product in which the one component is coated with asustained and/or enteric release polymer, and the other component isalso coated with a polymer such as a low viscosity grade ofhydroxypropyl methylcellulose (HPMC) or other appropriate materials asknown in the art, in order to further separate the active components.The polymer coating serves to form an additional barrier to interactionwith the other component.

These as well as other ways of minimizing contact between the componentsof combination products of the present invention, whether administeredin a single dosage form or administered in separate forms but at thesame time by the same manner, will be readily apparent to those skilledin the art, once armed with the present disclosure.

The compounds of the present invention can be administered alone or incombination with one or more additional therapeutic agents. By“administered in combination” or “combination therapy” it is meant thatthe compound of the present invention and one or more additionaltherapeutic agents are administered concurrently to the mammal beingtreated. When administered in combination, each component may beadministered at the same time or sequentially in any order at differentpoints in time. Thus, each component may be administered separately butsufficiently closely in time so as to provide the desired therapeuticeffect.

The compounds of the present invention are also useful as standard orreference compounds, for example as a quality standard or control, intests or assays involving the APJ receptor and apelin activity. Suchcompounds may be provided in a commercial kit, for example, for use inpharmaceutical research involving APJ and apelin or anti-heart failureactivity. For example, a compound of the present invention could be usedas a reference in an assay to compare its known activity to a compoundwith an unknown activity. This would ensure the experimenter that theassay was being performed properly and provide a basis for comparison,especially if the test compound was a derivative of the referencecompound. When developing new assays or protocols, compounds accordingto the present invention could be used to test their effectiveness.

The compounds of the present invention may also be used in diagnosticassays involving APJ and apelin.

The present invention also encompasses an article of manufacture. Asused. herein, article of manufacture is intended to include, but not belimited to, kits and packages. The article of manufacture of the presentinvention, comprises: (a) a first container; (b) a pharmaceuticalcomposition located within the first container, wherein the composition,comprises a first therapeutic agent, comprising a compound of thepresent invention or a pharmaceutically acceptable salt form thereof;and, (c) a package insert stating that the pharmaceutical compositioncan be used for the treatment and/or prophylaxis of multiple diseases ordisorders associated with APJ and apelin (as defined previously). Inanother embodiment, the package insert states that the pharmaceuticalcomposition can be used in combination (as defined previously) with asecond therapeutic agent for the treatment and/or prophylaxis ofmultiple diseases or disorders associated with APJ and apelin. Thearticle of manufacture can further comprise: (d) a second container,wherein components (a) and (b) are located within the second containerand component (c) is located within or outside of the second container.Located within the first and second containers means that the respectivecontainer holds the item within its boundaries.

The first container is a receptacle used to hold a pharmaceuticalcomposition. This container can be for manufacturing, storing, shipping,and/or individual/bulk selling. First container is intended to cover abottle, jar, vial, flask, syringe, tube (e.g., for a cream preparation),or any other container used to manufacture, hold, store, or distribute apharmaceutical product.

The second container is one used to hold the first container and,optionally, the package insert. Examples of the second containerinclude, but are not limited to, boxes (e.g., cardboard or plastic),crates, cartons, bags (e.g., paper or plastic bags), pouches, and sacks.The package insert can be physically attached to the outside of thefirst container via tape, glue, staple, or another method of attachment,or it can rest inside the second container without any physical means ofattachment to the first container. Alternatively, the package insert islocated on the outside of the second container. When located on theoutside of the second container, it is preferable that the packageinsert is physically attached via tape, glue, staple, or another methodof attachment. Alternatively, it can be adjacent to or touching theoutside of the second container without being physically attached.

The package insert is a label, tag, marker, etc. that recitesinformation relating to the pharmaceutical composition located withinthe first container. The information recited will usually be determinedby the regulatory agency governing the area in which the article ofmanufacture is to be sold (e.g., the United States Food and DrugAdministration). Preferably, the package insert specifically recites theindications for which the pharmaceutical composition has been approved.The package insert may be made of any material on which a person canread information contained therein or thereon. Preferably, the packageinsert is a printable material (e.g., paper, plastic, cardboard, foil,adhesive-backed paper or plastic, etc.) on which the desired informationhas been formed (e.g., printed or applied).

Other features of the invention will become apparent in the course ofthe following descriptions of exemplary embodiments that are given forillustration of the invention and are not intended to be limitingthereof.

VI. EXAMPLES

The following Examples are offered as illustrative, as a partial scopeand particular embodiments of the invention and are not meant to belimiting of the scope of the invention. Abbreviations and chemicalsymbols have their usual and customary meanings unless otherwiseindicated. Unless otherwise indicated, the compounds described hereinhave been prepared, isolated and characterized using the schemes andother methods disclosed herein or may be prepared using the same.

As a person of ordinary skill in the art would be able to understandthat a pyridone in a molecule may tautomerize to its keto and enol formsas shown in the following equation, wherein R¹, R², R³ and R⁴ are asdefined above, this disclosure is intended to cover all possibletautomers even when a structure depicts only one of them.

Description of Analytical LCMS Methods:

Method A: Waters Acquity UPLC BEH C18, 2.1×50 mm, 1.7 μm particles;Mobile Phase A: water with 0.05% TFA; Mobile Phase B: ACN with 0.05%TFA; Gradient: 2-98% B over 1 minute, then a 0.5 minute hold at 98% B;Flow: 0.8 mL/min; Detection: UV at 220 nm.

Method B: Column: Waters Acquity UPLC BEH C18, 2.1×50 mm, 1.7 μmparticles; Mobile Phase A: 5:95 ACN:water with 10 mM NH₄OAc; MobilePhase B: 95:5 ACN:water with 10 mM NH₄OAc; Temperature: 50° C.;Gradient: 0-100% B over 3 minutes, then a 0.75 minute hold at 100% B;Flow: 1.11 mL/min; Detection: UV at 220 nm.

Example 001:(S)-(6-butyl-5-(ethyl(phenyl)amino)-2,4-dihydroxypyridin-3-yl)(3-phenylpyrrolidin-1-yl)methanone

Example 001A: ethyl 2-bromo-3-oxoheptanoate

Sodium ethoxide (10.8 ml, 29.0 mmol) was dissolved in EtOH (58.1 ml).Ethyl 3-oxoheptanoate (5.15 ml, 29.0 mmol) was added followed bydropwise addition of bromine (1.50 ml, 29.0 mmol). After 1 hour, thereaction was diluted with water and extracted twice with DCM. Thecombined organic layers were washed with brine, dried with sodiumsulfate, filtered, and concentrated in vacuo. The residue was purifiedby column chromatography (ISCO, 80 g silica gel column, 29 minutegradient from 0 to 30% EtOAc in hexanes) to yield Example 001A (6.56 g,26.1 mmol, 90%) as a clear oil. LC/MS (Method A) RT=0.96 min, MS (ESI)m/z: 251.0 (M+H)⁺. ¹H NMR (400 MHz, CHLOROFORM-d) δ 4.78 (s, 1H), 4.28(q, J=7.1 Hz, 2H), 2.75 (td, J=7.3, 3.4 Hz, 2H), 1.65-1.53 (m, 3H), 1.31(t, J=7.0 Hz, 3H), 0.98-0.86 (m, 4H).

Example 001B: (E)-ethyl 2-(ethyl(phenyl)amino)-3-hydroxyhept-2-enoate

Example 001A (1.35 g, 5.37 mmol) and N-ethylaniline (0.650 g, 5.37 mmol)were dissolved in EtOH (10.73 ml) and heated to reflux for 14 h. Thereaction mixture was concentrated in vacuo. The residue was dissolved inEtOAc, washed with water, washed with brine, dried with sodium sulfate,filtered, and concentrated in vacuo. The residue was purified by columnchromatography (ISCO, 80 g silica gel column, 29 minute gradient from 0to 100% DCM in hexanes) to yield Example 001B (0.876 g, 3.01 mmol,56.0%) LC/MS (Method A) RT=1.23 min, MS (ESI) m/z: 292.3(M+H)⁺. ¹H NMR(400 MHz, CHLOROFORM-d) δ 12.60 (s, 1H), 7.22-7.15 (m, 2H), 6.73-6.67(m, 1H), 6.63 (dd, J=8.8, 0.9 Hz, 2H), 4.25-4.12 (m, 2H), 351-3.32 (m,2H), 2.37-2.21 (m, 2H), 1.28-1.24 (m, 2H), 1.19 (t, J=7.2 Hz, 3H), 1.12(t, J=7.2 Hz, 3H), 0.98-0.89 (m, 2H), 0.84 (t, J=7.3 Hz, 3H)

Example 001C: (E)-ethyl 3-amino-2-(ethyl(phenyl)amino)hept-2-enoate

Example 001B (0.943 g, 3.24 mmol) and ammonium acetate (2.50 g, 32.4mmol) were dissolved in MeOH (16.18 ml). The reaction mixture wasallowed to stir at 50° C. for 14 h. The reaction mixture wasconcentrated under reduced pressure and the residue was dissolved inEtOAc and water. The layers were separated and the organic layer waswashed with brine, dried with sodium sulfate, and concentrated underreduced pressure. The residue was purified by column chromatography(ISCO, dry load, 80 g silica gel column, 29 minute gradient from 0 to100% EtOAc in hexanes) to yield Example 001C (0.552 g, 1.90 mmol, 58.7%yield) as a pale yellow oil. LC/MS (Method A) RT=1.068 min, MS (ESI)m/z: 291.2 (M+H)⁺. ¹H NMR (400 MHz, CHLOROFORM-d) δ 7.20-7.06 (m, 2H),6.79-6.49 (m, 3H), 4.28-3.90 (m, 2H), 3.59-3.23 (m, 2H), 2.32-2.18 (m,2H), 1.50-1.38 (m, 2H), 1.36-1.22 (m, 4H), 1.22-1.15 (m, 3H), 1.11-1.05(m, 3H), 0.87-0.81 (m, 3H).

Example 001D: ethyl6-butyl-5-(ethyl(phenyl)amino)-2,4-dihydroxynicotinate

Example 001C (0.348 g, 1.20 mmol) was dissolved in DCM (5.99 ml) andsodium bicarbonate (5.99 ml, 5.99 mmol) added. Ethyl malonylchloride(0.453 ml, 3.60 mmol) was dissolved in 0.5 mL DCM and added dropwise.The reaction mixture was stirred at ambient temperature for 3 hours. Thereaction mixture was diluted with saturated NH₄Cl and washed thrice withDCM. The combined organic layers were washed with brine, dried (Na₂SO₄),filtered, and concentrated in vacuo. To the residue was added EtOH (5.99ml) and sodium ethoxide (1.790 ml, 4.79 mmol). The reaction mixture wasallowed to stir at ambient temperature overnight and concentrated underreduced pressure. The residue was diluted with 1 N HCl and DCM. Thelayers were separated and the aqueous layer was back extracted with DCM(×2). The combined organic layer was washed with brine, dried withsodium sulfate, filtered and concentrated under reduced pressure. Theresidue was purified on ISCO using 80 g column eluting with EtOAc in DCM0-100% to yield Example 001D (0.225 g, 0.628 mmol, 52.4% yield). LC/MS(Method A) RT=0.968 min, MS (ESI) m/z: 359.1 (M+H)⁺. ¹H NMR (400 MHz,CHLOROFORM-d) δ 13.66 (br. s., 1H), 10.37 (br. s., 1H), 7.24-7.13 (m,2H), 6.75 (t, J=7.3 Hz, 1H), 6.64-6.56 (m, 2H), 4.43 (q, J=7.2 Hz, 2H),3.57 (dd, J=9.9, 7.3 Hz, 2H) 2.66-2.47 (m, 2H), 1.65-1.57 (m, 2H), 1.41(t, J=7.0 Hz, 3H), 1.39-1.30 (m, 2H), 1.23 (t, J=7.2 Hz, 3H), 0.86 (t,J=7.4 Hz, 3H).

Example 001:(S)-(6-butyl-5-(ethyl(phenyl)amino)-2,4-dihydroxypyridin-3-yl)(3-phenylpyrrolidin-1-yl)methanone

To a solution of Example 001D (0.015 g, 0.042 mmol) and(S)-3-phenylpyrrolidine hydrochloride (7.7 mg, 0.042 mmol) in toluene(0.697 ml) was added TEA (0.012 ml, 0.084 mmol). The reaction mixturewas stirred for 5 min. To the stirred reaction was added HOAt (3.4 mg,0.025 mmol) followed zirconium(IV) tert-butoxide (9.8 μl, 0.025 mmol).The reaction was stirred at 100° C. for 14 h. The reaction mixture wasquenched by the addition of 1N HCl (3 mL) at RT. The reaction mixturewas extracted with DCM. The combined organic layers were dried andconcentrated, the residue was dissolved in DMF and purified viapreparative LC/MS with the following conditions: Column: Xbridge C18,19×200 mm, 5-μm particles; Mobile Phase A: 5:95 acetonitrile:water with10-mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile:water with10-mM ammonium acetate; Gradient: 30-70% B over 20 minutes, then a5-minute hold at 100% B; Flow: 20 mL/min to yield Example 001 (0.0084 g,0.018 mmol, 42.8% yield): LC/MS (Method A) RT=0.973 min, MS (ESI) m/z:460.2 (M+H)⁺. ¹H NMR (500 MHz, DMSO-d₆) δ 7.33 (br. s., 4H), 7.24 (br.s., 1H), 7.14 (br. s., 2H), 6.64 (br. s., 1H), 6.55 (d, J=8.0 Hz, 2H),4.01-3.35 (m, 4H), 3.17 (d, J=4.8 Hz, 1H), 2.55 (s, 2H), 2.34-1.89 (m,4H), 1.41 (br. s., 2H), 1.20-1.06 (m, 5H), 0.71 (br. s., 3H)) (2exchangeable protons were not observed). Human APJ cAMP Potency range B.

Example 002:(S)-(6-butyl-5-(ethyl(phenyl)amino)-2,4-dihydroxypyridin-3-yl)(3-phenylpyrrolidin-1-yl)methanone

Example 002A: (E)-ethyl3-(2-((4-bromophenyl)sulfonyl)acetamido)-2-(ethyl(phenyl)amino)hept-2-enoate

Example 001C (532 mg, 1.83 mmol) was dissolved in THF (18.300 ml) andpotassium carbonate (1270 mg, 9.16 mmol) was added to the reactionmixture. 2-((4-bromophenyl)sulfonyl)acetyl chloride (1090 mg, 3.66 mmol)was added, and the reaction mixture was allowed to stir for 14 h. Thereaction mixture was diluted with saturated NH₄Cl and extracted thricewith DCM. The combined organic layers were washed with brine, dried(Na₂SO₄), filtered, and concentrated in vacuo. The residue was purifiedby column chromatography (ISCO, 40 g silica gel column, 19 minutegradient from 0 to 50% EtOAc in hexanes) to yield Example 002A (0.668 g,1.21 mmol, 66.1% yield) as a yellow solid. LC/MS (Method A) RT=1.10 min,MS (ESI) m/z: 551.1 (M+H)³⁰ . ¹H NMR (400 MHz, CHLOROFORM-d) δ 11.90 (s,1H), 7.88-7.82 (m, 2H), 7.73 (d, J=8.8 Hz, 2H), 7.20 (dd, J=8.8, 7.5 Hz,2H), 6.74 (t, J=7.3 Hz, 1H), 6.58 (dd, J=8.7, 1.0 Hz, 2H), 4.13 (s, 2H),4.12-4.05 (m, 2H), 3.41 (d, J=5.9 Hz, 2H), 2.86-2.71 (m, 2H), 1.35-1.23(m, 4H), 1.21 (t, J=7.2 Hz, 3H), 1.05 (t, J=7.0 Hz, 3H), 0.85-0.72 (m,3H).

Example 002B:3-((4-bromophenyl)sulfonyl)-6-butyl-5-(ethyl(phenyl)amino)pyridine-2,4-diol

Example 002A (688 mg, 1.25 mmol) was dissolved in THF (25.600 ml).Sodium hydride (100 mg, 2.50 mmol, 60% dispersion in mineral oil) wasadded, and the reaction mixture was allowed to stir for 14 h at ambienttemperature. The reaction mixture was diluted with EtOAc and washed with1 N HCl, water, then brine, dried (Na₂SO₄), filtered, and concentratedin vacuo. The residue was purified by column chromatography (ISCO, 24 gsilica gel column, 19 minute gradient from 0 to 100% EtOAc in hexanes)to yield Example 002B (309 mg, 0.611 mmol, 49.0% yield). LC/MS (MethodA) RT=1.09 min, MS (ESI) m/z: 505.0 (M+H)⁺. ¹H NMR (500 MHz,CHLOROFORM-d) δ 11.53 (s, 1H), 10.64 (br. s., 1H), 7.96 (d, J=8.5 Hz,2H), 7.67 (d, J=8.5 Hz, 2H), 7.28-7.25 (m, 2H), 6.85 (t, J=7.3 Hz, 1H),6.62 (d, J=7.7 Hz, 2H), 2.72-2.41 (m, 2H), 1.63-1.59 (m, 2H), 1.43-1.24(m, 5H), 0.96-0.79 (m, 5H).

Example 002:6-butyl-5-(ethyl(phenyl)amino)-3-((4-(6-fluoropyridin-3-yl)phenyl)sulfonyl)pyridine-2,4-diol

Example 002B (15 mg, 0.030 mmol), (6-fluoropyridin-3-yl)boronic acid (13mg, 0.089 mmol), and PdCl₂(dppf)-CH₂Cl₂Adduct (2.42 mg, 2.97 μmol) weredissolved in THF (848 μl) and 1.5 M aq. sodium carbonate (59 μl, 0.089mmol) was added. The reaction mixture was degassed with nitrogen for 10minutes. The reaction mixture was then sealed and heated under microwaveirradiation for 30 minutes at 110° C. The reaction mixture was filteredand concentrated in vacuo. The residue was dissolved in DMF, filtered,and purified via preparative LC/MS with the following conditions:Column: XBridge C18, 19× mm, 5-μm particles; Mobile Phase A: 5:95acetonitrile:water with 10-mM ammonium acetate; Mobile Phase B: 95:5acetonitrile:water with 10-mM ammonium acetate; Gradient: 20-60% B over20 minutes, then a 4-minute hold at 100% B; Flow: 20 mL/min to yieldExample 002 (9.8 mg, 0.018 mmol, 62% yield): LC/MS (Method A) RT=1.07min, MS (ESI) m/z: 522.2 (M+H)⁻. ¹H NMR (500 MHz, DMSO-d₆) δ 8.60 (br.s., 1H), 8.34 (br. s., 1H), 8.00 (d, J=8.0 Hz, 2H), 7.84 (d, J=7.8 Hz,2H), 7.32 (d, J=6.3 Hz, 1H), 7.06 (t, J=7.6 Hz, 2H), 6.55 (t, J=6.9 Hz,1H), 6.48 (d, J=8.0 Hz, 2H), 2.33-2.11 (m, 2H), 1.40 (br. s., 2H), 1.23(s, 2H), 1.16 (d, J=7.2 Hz, 2H), 1.08 (t, J=7.0 Hz, 3H), 0.72 (t, J=7.3Hz, 3H) (2 exchangeable protons were not observed). Human APJ cAMPPotency range A.

Example 003:1-(4-((6-butyl-5-(ethyl(phenyl)amino)-2,4-dihydroxypyridin-3-yl)sulfonyl)phenyl)-5-methylpyridin-2(1H)-one

Example 002B (18 mg, 0.035 mmol), 5-methylpyridin-2(1H)-one (7.6 mg,0.069 mmol), and copper (II) acetate (6.3 mg, 0.035 mmol) were dissolvedin DMSO (989 μL) and DBU (10 μL, 0.069 mmol). The reaction mixture wasdegassed with nitrogen for 10 minutes. The reaction mixture was sealedand heated to 140° C. and allowed to stir for 14 h. The residue wasdiluted in DMSO, filtered, and purified via preparative LC/MS with thefollowing conditions: Column: XBridge C18, 19×200 mm, 5-μm particles;Mobile Phase A: 5:95 acetonitrile:water with 10-mM ammonium acetate;Mobile Phase B: 95:5 acetonitrile:water with 10-mM ammonium acetate;Gradient: 15-55% B over 19 minutes, then a 5-minute hold at 100% B;Flow: 20 mL/min to yield Example 003 (10.1 mg, 0.0190 mmol, 54.1%yield): LC/MS (Method A) RT=1.01 min, MS (ESI) m/z: 534.2 (M+H)⁺. ¹H NMR(500 MHz, DMSO-d₆) δ 8.28-7.80 (m, 2H), 7.56-7.28 (m, 5H), 7.03 (br. s.,2H), 6.44 (d, J=8.8 Hz, 3H), 3.94-3.06 (m, 2H), 2.30-2.10 (m, 2H), 2.05(s, 3H), 1.39 (br. s., 2H), 1.21-0.99 (m, 5H), 0.73 (br. s., 3H) (2exchangeable protons were not observed). Human APJ cAMP Potency range A.

Example 004:6-butyl-3-((4-cyclopropylphenyl)sulfonyl)-5-(ethyl(phenyl)amino)pyridine-2,4-diol

Example 002B (17.5 mg, 0.0350 mmol), cyclopropylboronic acid (17.8 mg,0.208 mmol), PdOAc₂ (3.11 mg, 0.0140 mmol), tricyclohexylphosponiumtetrafluoroborate (10.20 mg, 0.0280 mmol), and tripotassium phosphate(29.4 mg, 0.138 mmol) were dissolved in toluene (989 μl) and degassedwith nitrogen for 10 minutes. The reaction mixture vessel was sealed andheated for 60 minutes under microwave irradiation at 140° C. Thereaction mixture was filtered and concentrated in vacuo. The residue wasdissolved in DMF, filtered, and purified via preparative LC/MS with thefollowing conditions: Column: XBridge C18, 19×200 mm, 5-μm particles;Mobile Phase A: 5:95 acetonitrile:water with 10-mM ammonium acetate;Mobile Phase B: 95:5 acetonitrile:water with 10-mM ammonium acetate;Gradient: 30-70% B over 20 minutes, then a 5-minute hold at 100% B;Flow: 20 mL/min to yield Example 004 (5.4 mg, 0.011 mmol, 33% yield):LC/MS (Method A) RT=1.11 min, MS (ESI) m/z: 467.2 (M+H)⁺. ¹H NMR (600MHz, DMSO-d₆) δ 7.84 (d, J=7.1 Hz, 2H), 7.36-7.24 (m, 2H), 7.14 (br. s.,2H), 6.66 (br. s., 1H), 6.60-6.51 (m, 2H), 2.44-2.20 (m, 2H), 2.07 (s,1H), 1.51 (br. s., 1H), 1.44-1.35 (m, 3H), 1.19-1.11 (m, 4H), 1.06 (d,J=6.9 Hz, 2H), 0.86 (s, 1H), 0.80 (br. s., 2H), 0.72 (t, J=7.4 Hz, 3H)(2 exchangeable protons were not observed). Human APJ cAMP Potency rangeA.

Example 005:3-((2-butyl-5-((4-(2-fluoro-3-methylpyridin-4-yl)phenyl)sulfonyl)-4,6-dihydroxypyridin-3-yl)(methyl)amino)benzonitrile

Example 005A: ethyl 2-((3-cyanophenyl)(methyl)amino)acetate

Ethyl 2-bromoacetate (0.50 mL, 4.5 mmol), 3-(methylamino)benzonitrile(0.596 g, 4.51 mmol), and potassium carbonate (3.12 g, 22.5 mmol) weredissolved in Water (12.88 mL) and heated to 70° C. for 14 h. Reactionwas diluted with water and. EtOAc. The layers were separated and theorganic layer was washed with brine, dried with sodium sulfate andconcentrated under reduced pressure. The residue was purified on ISCOusing a 40 g column eluting with 0-100% EtOAc in hexanes to yield ethylExample 005A (0.600 g, 2.75 mmol, 61.0% yield) as a pale yellow oil.LC/MS (Method A) RT=1.01 min, MS (ESI) m/z: 219.1 (M+H)⁺. ¹H NMR (500MHz, CHLOROFORM-d) δ 7.33-7.29 (m, 1H), 7.03 (d, J=7.4 Hz, 1H),6.91-6.89 (m, 1H), 6.80-6.79 (m, 1H), 4.22 (q, J=7.2 Hz, 2H), 4.09 (s,2H), 3.11 (s, 3H), 1.29 (t, J=7.0 Hz, 3H).

Example 005B: ethyl 2-((3-cyanophenyl)(methyl)amino)-3-oxoheptanoate

Example 005A (0.245 g, 1.12 mmol) was dissolved in THF (11.23 ml) andcooled to −78° C. To the cooled solution was added LHMDS (0.133 mL, 1.12mmol) and the reaction mixture was allowed to stir for 25 min. Pentanoylchloride (0.133 ml, 1.12 mmol) was added, and the reaction mixture wasallowed to slowly warm to ambient temperature over 1 hour. The reactionmixture was diluted with water and EtOAc. The layers were separated andthe organic layer was washed with brine, dried with sodium sulfate, andconcentrated under reduced pressure. The residue was purified on ISCOusing 0-100% EtOAc in hexanes on a 40 g column to yield Example 005B(0.150 g, 0.496 mmol, 44.2% yield) as a colorless oil. LC/MS (Method A)RT=1.30 min, MS (ESI) m/z: 303.2 (M+H)⁺. ¹H NMR (400 MHz, CHLOROFORM-d)δ 12.34 (s, 1H), 7.17 (d, J=7.9 Hz, 1H), 6.93 (dt, J=7.6, 1.0 Hz, 1H),6.80-6.76 (m, 1H), 6.76-6.72 (m, 1H), 4.17-3.97 (m, 2H), 2.98 (s, 3H),2.27-2.12 (m, 2H), 1.54-1.47 (m, 2H), 1.23 (dt, J=15.0, 7.5 Hz, 2H),1.05 (t, J=7.0 Hz, 3H), 0.79 (t, J=7.4 Hz, 3H).

Example 005C: (E)-ethyl3-amino-2-((3-cyanophenyl)(methyl)amino)hept-2-enoate

Example 005B (0.150 g, 0.496 mmol) and ammonium acetate (0.765 g, 9.92mmol) were dissolved in EtOH (4.96 ml) and heated to 100° C. Thereaction mixture was stirred overnight. The reaction mixture wasconcentrated and dissolved in EtOAc and water. The layers were separatedand the organic layer was washed with water, washed with brine, driedwith sodium sulfate, and concentrated under reduced pressure. Theresidue was purified on ISCO using 40 g column eluting with 0-100% EtOAcin hexanes to yield Example 005C (0.137 g, 0.455 mmol, 92% yield). LC/MS(Method A) RT=1.27 min, MS (ESI) m/z: 302.2 (M+H)⁺. ¹H NMR (400 MHz,CHLOROFORM-d) δ 7.27-7.20 (m, 1H), 6.96 (dt, J=7.5, 1.1 Hz, 1H),6.88-6.86 (m, 1H), 6.85-6.81 (m, 1H), 4.21-3.97 (m, 2H), 3.06 (s, 3H),2.34-2.11 (m, 2H), 1.52-1.42 (m, 2H), 1.38-1.24 (m, 2H), 1.08 (t, J=7.2Hz, 3H), 0.88 (t, J=7.3 Hz, 3H) (2 exchangeable protons were notobserved).

Example 005D: (E)-ethyl3-(2-((4-bromophenyl)sulfonyl)acetamido)-2-((3-cyanophenyl)(methyl)amino)hept-2-enoate

Example 005C (0.137 g, 0.455 mmol) was dissolved in THF (4.55 ml) andpotassium carbonate (0.314 g, 2.27 mmol) was added.2-((4-bromophenyl)sulfonyl)acetyl chloride (0.271 g, 0.909 mmol) wasadded and the reaction mixture allowed to stir for 14 h. The reactionmixture was diluted with saturated NH₄Cl and extracted thrice with DCM.The combined organic layers were washed with brine, dried (Na₂SO₄),filtered, and concentrated in vacuo. The residue was purified by columnchromatography (ISCO, 40 g silica gel column, 19 minute gradient from 0to 50% EtOAc in hexanes) to yield. Example 005D (0.205 g, 0.364 mmol,80% yield). LC/MS (Method A) RT=1.24 min, MS (ESI) m/z: 562.2 (M+H)⁺. ¹HNMR (400 MHz, CHLOROFORM-d) δ 7.88-7.85 (m, 2H), 7.79-7.75 (m, 2H),7.32-7.29 (m, 1H), 7.09-7.05 (m, 1H), 6.85-6.83 (m, 1H), 6.79 (dd,J=8.0, 2.3 Hz, 1H), 4.18-4.15 (m, 2H), 4.14 (d, J=2.4 Hz, 1H), 3.07 (s,3H), 2.89-2.65 (m, 2H), 1.43-1.24 (m, 6H), 1.08 (t, J=7.0 Hz, 3H), 0.84(t, J=7.3 Hz, 3H).

Example 005E:3-((5-((4-bromophenyl)sulfonyl)-2-butyl-4,6-dihydroxypyridin-3-yl)(methyl)amino)benzonitrile

Example 005D (205 mg, 0.364 mmol) was dissolved in THF (6.00 ml). Sodiumhydride (29.2 mg, 0.729 mmol, 60% dispersion in mineral oil) was addedand the reaction was allowed to stir overnight. The reaction was dilutedwith EtOAc and washed with 1 N HCl, water, then brine, dried (Na₂SO₄),filtered, and concentrated in vacuo. The crude material was purified bycolumn chromatography (ISCO, 24 g silica gel column, 19 minute gradientfrom 0 to 100% EtOAc in hexanes) to yield Example 005E (0.122 g, 0.236mmol, 64.8% yield). LC/MS (Method A) RT=1.15 min, MS (ESI) m/z: 516.1(M+H)⁺. ¹H NMR (400 MHz, CHLOROFORM-d) δ 11.60 (s, 1H), 10.92-10.74 (m,1H), 7.95 (d, J=8.8 Hz, 2H), 7.69 (d, J=8.8 Hz, 2H), 7.39-7.30 (m, 1H),7.12 (d, J=7.9 Hz, 1H), 6.89-6.84 (m, 1H), 6.80 (dd, J=8.0, 2.3 Hz, 1H),3.22 (s, 3H), 2.59-2.40 (m, 2H), 1.66-1.58 (m, 2H), 1.43-1.32 (m, 2H),0.92 (t, J=7.3 Hz, 3H).

Example 005:3-((2-butyl-5-((4-(2-fluoro-3-methylpyridin-4-yl)phenyl)sulfonyl)-4,6-dihydroxypyridin-3-yl)(methyl)amino)benzonitrile

Example 005E (15 mg, 0.029 mmol), (2-fluoro-3-methylpyridin-4-yl)boronicacid (13.50 mg, 0.08700 mmol), and PdCl₂(dppf)-CH₂Cl₂ adduct (2.37 mg,2.90 μmol) were dissolved in THF (830 μL) and 1.5 M aqueous sodiumcarbonate (58.1 μL, 0.0870 mmol) was added. The reaction mixture wasdegassed with nitrogen for 10 minutes. The reaction mixture vessel wasthen sealed and heated under microwave irradiation for 30 minutes at110° C. The reaction mixture was filtered and concentrated in vacuo. Theresidue was dissolved in DMF, filtered, and purified via preparativeLC/MS with the following conditions: Column: XBridge C18, 19×200 mm,5-μm particles; Mobile Phase A: 5:95 acetonitrile:water with 10-mMammonium acetate; Mobile Phase B: 95:5 acetonitrile:water with 10-mMammonium acetate; Gradient: 15-55% B over 20 minutes, then a 5-minutehold at 100% B; Flow: 20 mL/min to yield AB-005 (11 mg, 0.020 mmol, 69%yield): LC/MS (Method A) RT=1.03 min, MS (ESI) m/z: 547.0 (M+H)⁺. ¹H NMR(500 MHz, DMSO-d₆) δ 8.17-8.09 (m, 1H), 8.01 (d, J=7.6 Hz, 2H), 7.54 (d,J=7.6 Hz, 2H), 7.26 (br. s., 2H), 6.97 (d, J=7.3 Hz, 1H), 6.83-6.73 (m,2H), 3.02 (s, 3H), 2.15 (s, 5H), 1.40 (br. s., 2H), 1.24-1.13 (m, 2H),0.75 (t, J=7.2 Hz, 3H) (2 exchangeable protons were not observed). HumanAPJ cAMP Potency range A.

Example 006:(6-butyl-5-((2-fluorophenyl)(methyl)amino)-2,4-dihydroxypyridin-3-yl)(3-(3,5-difluoropyridin-2-yl)pyrrolidin-1-yl)methanone

Example 006A: benzyl 2-((2-fluorophenyl)(methyl)amino)acetate

Benzyl 2-bromoacetate (0.50 mL, 3.2 mmol), 2-fluoro-N-methylaniline0.399 g, 3.19 mmol), and potassium carbonate (2.202 g, 15.93 mmol) weredissolved in water (9.11 mL) and heated to 70° C. for 14 h. The reactionmixture was diluted with water and EtOAc. The layers were separated andthe organic layer was washed with brine, dried with sodium sulfate andconcentrated under reduced pressure. The residue was purified on ISCO0-100% EtOAc in hexanes on a 40 g column to yield Example 006A (0.750 g,2.33 mmol, 73.2% yield). Compound 006A was used without furtherpurification. LC/MS (Method A) RT=1.14 min, MS (ESI) m/z: 274.1 (M+H)⁺.

Example 006B: benzyl 2-((2-fluorophenyl)(methyl)amino)-3-oxoheptanoate

Example 006A (0.750 g, 2.74 mmol) was dissolved in THF (27.4 ml) andcooled to −78° C. To the cooled solution was added LHMDS (5.49 ml, 5.49mmol). The reaction mixture was allowed to stir for 25 min and pentanoylchloride (0.326 ml, 2.74 mmol) was added dropwise. The reaction mixturewas allowed to slowly warm to ambient temperature over 1 hour. Thereaction mixture was diluted with water and EtOAc. The layers wereseparated and the organic layer was washed with brine, dried with sodiumsulfate, and concentrated under reduced pressure. The residue waspurified on ISCO using 80 g column eluting with 0-100% EtOAc in hexanesto yield Example 006B (0.202 g, 0.565 mmol, 21%). LC/MS (Method A)RT=1.34 min, MS (ESI) m/z: 358.2 (M+H)⁺. ¹H NMR (400 MHz, CHLOROFORM-d)δ 12.04 (s, 1H), 7.10-7.07 (m, 2H), 6.93 (ddd, J=4.3, 3.2, 2.2 Hz, 2H),6.78 (d, J=8.1 Hz, 3H), 6.63-6.53 (m, 2H), 5.01 (d, J=5.1 Hz, 2H), 2.92(d, J=2.2 Hz, 3H), 2.37-2.17 (m, 2H), 1.49-1.32 (m, 2H), 1.22-1.07 (m,2H), 0.71 (t, J=7.3 Hz, 3H).

Example 006C. (E)-benzyl3-amino-2-((2-fluorophenyl)(methyl)amino)hept-2-enoate

Example 006B (0.561 g, 1.57 mmol) and ammonium acetate (2.42 g, 31.4mmol) were dissolved in EtOH (15.70 ml) and heated to 100° C. Thereaction mixture was allowed to stir for 14 h. The reaction mixture wasconcentrated and dissolved in EtOAc and water. The layers were separatedand the organic layer was washed with water, washed with brine, driedwith sodium sulfate, and concentrated under reduced pressure. Theresidue was purified on ISCO using 40 g column eluting with 0-100% EtOAcin hexanes to yield Example 006C (0.332 g, 0.931 mmol, 59.3% yield).LC/MS (Method A) RT=1.29 min, MS (ESI) m/z: 357.2. (M+H)⁺. ¹H NMR (500MHz, CHLOROFORM-d) δ 7.28-7.21 (m, 4H), 7.11 (dd, J=7.3, 2.3 Hz, 2H),6.97-6.90 (m, 2H), 6.76-6.71 (m, 1H), 6.71-6.66 (m, 2H), 5.12 (d, J=9.6Hz, 2H), 3.13 (d, J=3.0 Hz, 3H), 2.51-2.31 (m, 2H), 1.54-1.46 (m, 2H),1.39-1.32 (m, 2H), 0.89 (t, J=7.3 Hz, 3H).

Example 006D: ethyl6-butyl-5-((2-fluorophenyl)(methyl)amino)-2,4-dihydroxynicotinate

Example 006C (0.100 g, 0.281 mmol) was dissolved in DCM (1.403 ml) andsodium bicarbonate (1.403 ml, 1.403 mmol) was added. Ethyl malonylchloride (0.106 ml, 0.842 mmol) was dissolved in 0.5 ml DCM and addeddropwise. The reaction mixture was stirred at ambient temperature for 14h. The reaction mixture was diluted with saturated NH₄Cl and washedthrice with DCM. The combined organic layers were washed with brine,dried (Na₂SO₄), filtered, and concentrated in vacuo. To the residue wasadded EtOH (1.403 ml) and sodium ethoxide (0.419 ml, 1.12 mmol). Thereaction mixture was allowed to stir at ambient temperature over 14 h.The reaction mixture was concentrated under reduced pressure. Theresidue was diluted with 1 N HCl and DCM. The layers were separated andthe aqueous layer was back extracted with DCM ×2. The combined organiclayer was washed with brine, dried with sodium sulfate, and concentratedunder reduced pressure. The residue was purified on ISCO using 80 gcolumn eluting with EtOAc in DCM 0-100% to yield Example 006D (0.041 g,0.113 mmol, 40.3% yield). LC/MS (Method A) RT=1.13 min, MS (ESI) m/z:363.2 (M+H)⁺. ¹H NMR (400 MHz, CHLOROFORM-d) δ 13.76 (s, 1H), 10.15-9.68(m, 1H), 7.07-7.01 (m, 1H), 6.96 (ddd, J=13.8, 8.0, 1.3 Hz, 1H),6.89-6.76 (m, 2H), 4.53-4.39 (m, 2H), 3.23 (d, J=1.8 Hz, 3H), 2.77-2.51(m, 2H), 1.67-1.59 (m, 2H), 1.44 (t, J=7.0 Hz, 3H), 1.39-1.30 (m, 2H),0.90 (t, J=7.3 Hz, 3H).

Example 006:(6-butyl-5-((2-fluorophenyl)(methyl)amino)-2,4-dihydroxypyridin-3-yl)(3-(3,5-difluoropyridin-2-yl)pyrrolidin-1-yl)methanone

To a solution of Example 006D (0.025 g, 0.069 mmol) and3,5-difluoro-2-(pyrrolidin-3-yl)pyridine (0.013 g, 0.069 mmol) intoluene (1.150 ml) was added TEA (0.019 ml, 0.14 mmol). The reactionmixture was stirred for 5 min. To the stirred reaction mixture was addedHOAt (5.63 mg, 0.0410 mmol) followed zirconium(IV) t-butoxide (0.016 ml,0.041 mmol). The reaction mixture was stirred at 100° C. for 14 h. Themixture was quenched by the addition of 1N HCl (3 mL) at ambienttemperature. The reaction mixture was extracted with DCM. The combinedorganic layers were dried and concentrated under reduced vacuum. Theresidue was dissolved in DMF, filtered, and purified via preparativeLC/MS with the following conditions: Column: XBridge C18, 19×200 mm,5-μm particles; Mobile Phase A: 5:95 acetonitrile:water with 10-mMammonium acetate; Mobile Phase B: 95:5 acetonitrile:water with 10-mMammonium acetate; Gradient: 30-70% B over 19 minutes, then a 5-minutehold at 100% B; Flow: 20 mL/min to yield Example 006 (4.1 mg, 8.2 μmol,12% yield). LC/MS (Method A) RT=0.95 min, MS (ESI) m/z: 501.3 (M+H)⁺. ¹HNMR (500 MHz, DMSO-d₆) δ 8.48 (br. s., 1H), 7.92 (br. s., 1H), 7.05 (br.s., 4H), 3.91 (s, 1H), 3.85-3.49 (m, 4H), 3.07 (s, 3H), 2.26 (d, J=7.3Hz, 4H), 1.46-1.06 (m, 4H), 0.71 (t, J=6.9 Hz, 3H) (2 exchangeableprotons were not observed). Human APJ cAMP Potency range A.

The compounds listed in the table below were synthesized using the abovedescribed methods.

TABLE 1 hAPJ LC/MS RT (min) cAMP EC₅₀ Ex # Structure Name ¹H NMR MethodM + H Potency range 007

(S)-(6-butyl-2,4- dihydroxy-5- (methyl(phenyl)a- mino)pyridin-3-yl)(3-phenylpyrrolidin-1- yl)methanone ¹H NMR (500 MHz, DMSO-d₆) ™ 7.31 (m,4H), 7.23 (d, J = 7.9 Hz, 1H), 7.16- 7.06 (m, 2H), 6.62 (t, J = 6.4 Hz,1H), 6.51 (m, 2H), 3.64 (m, 2H), 3.54-3.29 (m, 2H), 3.04 (m, 3H), 2.22(m, 3H), 2.00-1.84 (m, 2H), 1.40 (m, 2H), 1.15 (m, 2H), 0.72 (m, 3H) (2exchangeable protons not observed) 0.99 A 446.4 B 008

(R)-(6-butyl-2,4- dihydroxy-5- (methyl(phenyl)a- mino)pyridin-3-yl)(3-phenylpyrrolidin-1- yl)methanone ¹H NMR (500 MHz, DMSO-d₆) δ 7.31 (m,4H), 7.23 (m, 1H), 7.10 (m, 2H), 6.60 (m, 1H), 6.51 (m, 2H), 3.92-3.67(m, 1H), 3.64-3.29 (m, 1H), 3.04 (m, 3H), 2.55 (s, 3H), 2.22 (m, 3H),1.94 (m, 1H), 1.41 (m, 2H), 1.17 (m, 2H), 0.74 (m, 3H) (2 exchangeableprotons not observed) 0.99 A 446.4 B 009

(R)-(6-butyl-2,4- dihydroxy-5-(indolin-1- yl)pyridin-3-yl)(3-phenylpyrrolidin-1- yl)methanone ¹H NMR (500 MHz, DMSO-d₆) δ 7.39- 7.20(m, 5H), 7.10-7.03 (m, 1H), 6.89 (m, 1H), 6.56 (t, J = 7.1 Hz, 1H), 6.03(d, J = 8.0 Hz, 1H), 3.67 (m, 2H), 3.57-3.32 (m, 2H), 3.08 (m, 2H),2.49-2.42 (m, 2H), 2.40-2.19 (m, 3H), 2.07-1.88 (m, 2H), 1.47 (m, 2H),1.25-1.14 (m, 2H), 0.76 (m, 3H) (2 exchangeable protons not observed)0.98 A 458.2 B 010

3-((4- bromophenyl)sulfonyl)- 6-butyl-5- (methyl(phenyl)a-mino)pyridine-2,4-diol ¹H NMR (500 MHz, DMSO-d₆) δ 7.95 (d, J = 8.3 Hz,2H), 7.85 (d, J = 8.3 Hz, 2H), 7.17 (t, J = 7.7 Hz, 2H), 6.69 (t, J =7.2 Hz, 1H), 6.57 (d, J = 8.0 Hz, 2H), 3.09 (s, 3H), 2.37-2.26 (m, 2H),1.41 (dt, J = 15.1, 7.5 Hz, 2H), 1.22-1.14 (m, 2H), 0.73 (t, J = 7.3 Hz,3H) (2 exchangeable protons not observed) 1.02 A 491/493 B 011

6-butyl-3-((4-(2-fluoro- 3-methylpyridin-4-yl)phen-yl)sulfonyl)-5-(meth- yl(phenyl)amino)pyridine- 2,4-diol ¹H NMR (500MHz, DMSO-d₆) δ 8.13 (d, J = 4.6 Hz, 1H), 8.07 (d, J = 7.8 Hz, 2H), 7.61(d, J = 7.8 Hz, 2H), 7.27 (d, J = 4.6 Hz, 1H), 7.11 (t, J = 7.4 Hz, 2H),6.62 (t, J = 6.9 Hz, 1H), 6.52 (d, J = 7.7 Hz, 2H), 3.04 (s, 3H), 2.23(br. s., 2H), 2 .15 (s, 3H), 1.41 (dd, J = 15.0, 7.3 Hz, 2H), 1.23-1.11(m, 2H), 0.74 (t, J = 7.2 Hz, 3H) (2 exchangeable protons not observed)1.00 A 522.2 A 012

6-butyl-3-((4-(6- fluoropyridin-3- yl)phenyl)sulfonyl)-5-(meth-yl(phenyl)amino)pyridine- 2,4-diol ¹H NMR (500 MHz, DMSO-d₆) δ 8.62 (br.s., 1H), 8.40-8.33 (m, 1H), 8.07 (d, J = 8.2 Hz, 2H), 7.91 (d, J = 8.2Hz, 2H), 7.33 (d, J = 6.5 Hz, 1H), 7.13 (t, J = 7.7 Hz, 2H), 6.64 (t, J= 7.1 Hz, 1H), 6.53 (d, J = 8.0 Hz, 2H), 3.06 (s, 3H), 2.25 (d, J = 6.9Hz, 2H), 1.41 (dd, J = 15.4, 7.9 Hz, 2H), 1.22-1.10 (m, 2H), 0.74 (t, J= 7.3 Hz, 3H) (2 exchangeable protons not observed) 1.00 A 508.1 A 013

6-butyl-5-(indolin-1-yl)- 3-((4-(3-methylpyridin-4-yl)phenyl)sulfonyl)pyridine- 2,4-diol ¹H NMR (500 MHz, DMSO-d₆) δ 8.45(s, 1H), 8.40 (d, J = 4.3 Hz, 1H), 7.98 (d, J = 8.0 Hz, 2H), 7.48 (d, J= 8.1 Hz, 2H), 7.25 (d, J = 4.8 Hz, 1H), 6.96 (d, J = 6.9 Hz, 1H),6.83-6.77 (m, 1H), 6.49- 6.43 (m, 1H), 5.86 (d, J = 7.8 Hz, 1H),3.82-3.74 (m, 2H), 2.35 (d, J = 13.1 Hz, 2H), 2.29-2.23 (m, 2H), 2.20(br. s., 3H), 1.45-1.36 (m, 2H), 1.19 (dt, J = 14.7, 7.4 Hz, 2H),0.78-0.70 (m, 3H) (2 exchangeable protons not observed) 0.87 A 516.3 A014

6-butyl-5- (methyl(phenyl)amino)- 3-((4-(3-methylpyridin-4-yl)phenyl)sulfonyl)pyridine- 2,4-diol ¹H NMR (500 MHz, DMSO-d₆) δ 8.51(br. s., 2H), 7.97 (d, J = 7.9 Hz, 2H), 7.48 (d, J = 7.8 Hz, 2H), 7.26(br. s., 1H), 7.04 (t, J = 7.6 Hz, 2H), 6.52 (t, J = 7.0 Hz, 1H), 6.44(d, J = 7.9 Hz, 2H), 2.96 (s, 3H), 2.24 (s, 3H), 2.12 (t, J = 7.4 Hz,2H), 1.38 (d, J = 5.4 Hz, 2H), 1.22-1.12 (m, 2H), 0.75 (t, J = 7.3 Hz,3H) (2 exchangeable protons not observed) 0.97 A 504.3 A 015

6-butyl-3-((4-(6-fluoro- 2-methylpyridin-3- yl)phenyl)sulfonyl)-5-(methyl(phenyl)a- mino)pyridine-2,4-diol ¹H NMR (500 MHz, DMSO-d₆) δ8.08 (d, J = 8.2 Hz, 2H), 7.87 (t, J = 8.1 Hz, 1H), 7.64 (d, J = 8.2 Hz,2H), 7.16 (t, J = 7.8 Hz, 2H), 7.11 (dd, J = 8.2, 2.7 Hz, 1H), 6.67 (t,J = 7.3 Hz, 1H), 6.56 (d, J = 8.2 Hz, 2H), 3.09 (s, 3H), 2.38 (s, 3H),2.34-2.24 (m, 2H), 1.49-1.32 (m, 2H), 1.25-1.12 (m, 2H), 0.74 (t, J =7.3 Hz, 3H) (2 exchangeable protons not observed) 1.01 A 522.1 A 016

6-butyl-3-((4- cyclopropylphen- yl)sulfonyl)-5-(meth-yl(phenyl)amino)pyri- dine-2,4-diol ¹H NMR (500 MHz, DMSO-d₆) δ 7.75 (d,J = 8.2 Hz, 2H), 7.12 (d, J = 8.0 Hz, 2H), 7.05 (t, J = 7.6 Hz, 2H),6.54 (t, J = 7.1 Hz, 1H), 6.44 (d, J = 7.9 Hz, 2H), 2.96 (s, 3H), 2.13(t, J = 7.4 Hz, 2H), 1.95 (m, 1H), 1.37 (d, J = 5.0 Hz, 2H), 1.19-1.13(m, 2H), 0.99 (d, J = 6.6 Hz, 2H), 0.77-0.68 (m, 5H) (2 exchangeableprotons not observed) 1.62 B 453.2 A 017

6-butyl-5- (methyl(phenyl)amino)- 3-((4-(2-methylpyridin-3-yl)phenyl)sulfonyl)pyridine- 2,4-diol ¹H NMR (500 MHz, DMSO-d₆) δ 8.52(d, J = 3.9 Hz, 1H), 8.10 (d, J = 8.1 Hz, 2H), 7.71-7.63 (m, 3H), 7.35(dd, J = 7.3, 5.0 Hz, 1H), 7.17 (t, J = 7.7 Hz, 2H), 6.69 (t, J = 7.1Hz, 1H), 6.58 (d, J = 8.1 Hz, 2H), 3.10 (s, 3H), 2.44 (s, 3H), 2.37-2.23(m, 2H), 1.51-1.36 (m, 2H), 1.25-1.13 (m, 2H), 0.75 (t, J = 7.3 Hz, 3H)(2 exchangeable protons not observed) 0.82 A 504.2 A 018

1-(4-((6-butyl-2,4- dihydroxy-5- (methyl(phenyl)amino)pyridin-3-yl)sulfonyl)phenyl)-5- chloropyridin-2(1H)- one ¹H NMR (500 MHz,DMSO-d₆) δ 8.01 (d, J = 8.2 Hz, 2H), 7.96 (d, J = 2.6 Hz, 1H), 7.59 (dd,J = 9.9, 2.8 Hz, 1H), 7.52 (d, J = 8.2 Hz, 2H), 7.06 (t, J = 7.7 Hz,2H), 6.58-6.50 (m, 2H), 6.46 (d, J = 8.1 Hz, 2H), 2.97 (s, 3H), 2.13 (t,J = 7.7 Hz, 2H), 1.39 (br. s., 2H), 1.21-1.10 (m, 2H), 0.75 (t, J = 7.3Hz, 3H) (2 exchangeable protons not observed) 1.40 B 540.1 A 019

(S)-(6-butyl-5-(3,4- dihydroquinolin-1(2H)-yl)-2,4- dihydroxypyridin-3-yl)(3-phenylpyrrolidin- 1-yl)methanone ¹H NMR (500 MHz, DMSO-d₆) δ 7.33(d, J = 5.0 Hz, 4H), 7.27-7.22 (m, 1H), 6.93 (d, J = 7.3 Hz, 1H), 6.85(t, J = 7.3 Hz, 1H), 6.52 (t, J = 7.2 Hz, 1H), 6.14- 6.05 (m, 1H),3.79-3.48 (m, 6H), 3.22 (d, J = 5.2 Hz, 1H), 2.88-2.69 (m, 2H),2.39-2.31 (m, 2H), 2.26 (m, 1H), 2.08- 1.88 (m, 3H), 1.46 (m, 2H),1.28-1.16 (m, 2H), 0.77 (t, J = 7.2 Hz, 3H) (2 exchangeable protons notobserved) 1.07 A 472.3 B 020

6-butyl-3-((4-(2-fluoro- 3-methylpyridin-4- yl)phenyl)sulfonyl)-5-(isopropyl(phenyl)a- mino)pyridine-2,4-diol ¹H NMR (600 MHz, DMSO-d₆) δ8.14 (d, J = 4.8 Hz, 1H), 8.09 (br. s., 2H), 7.67 (br. s., 2H), 7.29 (d,J = 4.6 Hz, 1H), 7.13 (br. s., 2H), 6.64 (br. s., 1H), 6.56 (br. s.,2H), 4.12 (br. s., 1H), 4.05-3.87 (m, 2H), 2.43-2.20 (m, 2H), 2.16 (s,3H), 1.46-1.31 (m, 2H), 1.23 (s, 3H), 1.14 (br. s., 6H) (2 exchangeableprotons not observed) 1.12 A 550.2 A 021

6-butyl-5-(3,4- dihydroquinolin-1(2H)- yl)-3-((4-(6-fluoro-2-methylpyridin-3-yl)phen- yl)sulfonyl)pyridine- 2,4-diol ¹H NMR (600 MHz,DMSO-d₆) δ 8.07 (d, J = 7.7 Hz, 2H), 7.87 (t, J = 8.2 Hz, 1H), 7.64 (br.s., 2H), 7.11 (d, J = 8.3 Hz, 1H), 6.93 (d, J = 6.7 Hz, 1H), 6.86 (br.s., 1H), 6.52 (br. s., 1H), 6.12 (d, J = 7.9 Hz, 1H), 2.83-2.70 (m, 2H),2.38 (s, 3H), 2.36-2.24 (m, 2H), 2.03-1.88 (m, 2H), 1.53-1.40 (m, 2H),1.28-1.17 (m, 4H), 0.76 (t, J = 7.3 Hz, 3H) (2 exchangeable protons notobserved) 1.10 A 548.2 A 022

6-butyl-5-(3,4- dihydroquinolin-1(2H)- yl)-3-((4-(3-methylpyridin-4-yl)phen- yl)sulfonyl)pyridine- 2,4-diol ¹H NMR (500 MHz,DMSO-d₆) δ 8.51 (s, 1H), 8.46 (d, J = 5.0 Hz, 1H), 7.99- 7.93 (m, 2H),7.46 (d, J = 8.4 Hz, 2H), 7.24 (d, J = 5.0 Hz, 1H), 6.81 (d, J = 7.2 Hz,1H), 6.75-6.68 (m, 1H), 6.36 (td, J = 7.2, 0.8 Hz, 1H), 6.08-6.01 (m,1H), 3.58-3.50 (m, 1H), 3.06-2.99 (m, 1H), 2.81-2.61 (m, 2H), 2.24 (s,3H), 2.20- 2.09 (m, 2H), 1.97-1.82 (m, 2H), 1.42 (dtt, J = 11.3, 7.5,3.6 Hz, 2H), 1.21 (sxt, J = 7.4 Hz, 2H), 0.78 (t, J = 7.3 Hz, 3H) (2exchangeable protons not observed) 0.90 A 530.2 A 023

(R)-(6-butyl-2,4- dihydroxy-5- (isopropyl(phen- yl)amino)pyri-din-3-yl)(3- phenylpyrrolidin-1- yl)methanone ¹H NMR (500 MHz, DMSO-d₆)δ 7.39- 7.18 (m, 5H), 7.07 (br. s., 2H), 6.61- 6.45 (m, 3H), 4.18-3.23(m, 3H), 2.35- 2.13 (m, 3H), 1.98-1.82 (m, 4H), 1.42 (br. s., 2H),1.19-1.03 (m, 8H), 0.71 (d, J = 6.3 Hz, 3H) (2 exchangeable protons notobserved) 1.98 B 474.2 B 024

6-butyl-5-(3,4- dihydroquinolin-1(2H)- yl)-3-((4-(2-methylpyridin-3-yl)phen- yl)sulfonyl)pyridine- 2,4-diol ¹H NMR (500 MHz,DMSO-d₆) δ 8.51 (d, J = 4.1 Hz, 1H), 8.09 (d, J = 8.2 Hz, 2H), 7.72-7.62(m, 3H), 7.36 (dd, J = 7.4, 5.0 Hz, 1H), 6.94 (d, J = 7.3 Hz, 1H), 6.88(t, J = 7.7 Hz, 1H), 6.55 (t, J = 7.3 Hz, 1H), 6.14 (d, J = 8.1 Hz, 1H),3.50 (br. s., 1H), 3.29-3.17 (m, 1H), 2.88-2.66 (m, 2H), 2.44 (s, 3H),2.41- 2.30 (m, 2H), 2.04-1.88 (m, 2H), 1.50- 1.37 (m, 2H), 1.21 (dq, J =14.6, 7.2 Hz, 2H), 0.76 (t, J = 7.3 Hz, 3H) (2 exchangeable protons notobserved) 0.89 A 530.2 A 025

6-butyl-5- (isopropyl(phen- yl)amino)- 3-((4-(2-methyl-pyridin-3-yl)phen- yl)sulfonyl)pyri- dine-2,4-diol ¹H NMR (500 MHz,DMSO-d₆) δ 8.50 (d, J = 3.8 Hz, 1H), 8.05 (d, J = 8.0 Hz, 2H), 7.66 (dd,J = 17.3, 7.8 Hz, 3H), 7.35 (dd, J = 7.4, 4.8 Hz, 1H), 7.13 (t, J = 7.6Hz, 2H), 6.64 (t, J = 6.9 Hz, 1H), 6.57 (d, J = 8.2 Hz, 2H), 4.12 (br.s., 1H), 2.43 (s, 3H), 2.39 (d, J = 18.1 Hz, 1H), 2.25 (br. s., 1H),1.48-1.30 (m, 2H), 1.13 (dd, J = 14.0, 6.3 Hz, 8H), 0.69 (t, J = 7.3 Hz,3H) (2 exchangeable protons not observed) 0.90 A 532.2 A 026

6-butyl-3-((4-(6-fluoro- 2-methylpyridin-3- yl)phenyl)sulfonyl)-5-(isopropyl(phen- yl)amino)pyridine- 2,4-diol ¹H NMR (500 MHz, DMSO-d₆) δ11.82 (s, 1H), 11.32 (br. s., 1H), 8.12-8.06 (m, 2H), 7.91 (t, J = 8.2Hz, 1H), 7.72- 7.66 (m, 2H), 7.19-7.12 (m, 3H), 6.68 (t, J = 7.2 Hz,1H), 6.61 (d, J = 8.1 Hz, 2H), 4.17 (dt, J = 12.8, 6.4 Hz, 1H), 2.46-2.38 (m, 4H), 2.34-2.25 (m, 1H), 1.50- 1.32 (m, 2H), 1.21-1.09 (m, 8H),0.70 (t, J = 7.3 Hz, 3H) 1.11 A 550.2 A 027

6-butyl-5- (isopropyl(phen- yl)amino)- 3-((4-(3-methylpyridin-4-yl)phen- yl)sulfonyl)pyridine- 2,4-diol ¹H NMR (500 MHz,DMSO-d₆) δ 8.50 (br. s., 1H), 8.45 (d, J = 4.5 Hz, 1H), 7.94 (d, J = 8.0Hz, 2H), 7.48 (d, J = 7.9 Hz, 2H), 7.24 (d, J = 4.8 Hz, 1H), 7.03 (t, J= 7.7 Hz, 2H), 6.51 (t, J = 7.0 Hz, 1H), 6.46 (d, J = 8.2 Hz, 2H), 3.95(br. s., 1H), 2.26-2.03 (m, 5H), 1.46-1.33 (m, 2H), 1.20-1.11 (m, 2H),1.09 (d, J = 6.1 Hz, 3H), 0.99 (d, J = 6.2 Hz, 3H), 0.71 (t, J = 7.3 Hz,3H) (2 exchangeable protons not observed) 0.91 A 532.2 A 028

6-butyl-5-(3,4- dihydroquinolin-1(2H)- yl)-3-((4-(2-fluoro-3-methylpyridin-4-yl)phen- yl)sulfonyl)pyridine- 2,4-diol ¹H NMR (600 MHz,DMSO-d₆) δ 8.11 (d, J = 4.8 Hz, 1H), 8.01 (d, J = 8.1 Hz, 2H), 7.52 (d,J = 8.1 Hz, 2H), 7.25 (d, J = 4.8 Hz, 1H), 6.84 (d, J = 7.3 Hz, 1H),6.76 (t, J = 7.6 Hz, 1H), 6.41 (t, J = 7.2 Hz, 1H), 6.06 (d, J = 8.3 Hz,1H), 3.57- 3.45 (m, 1H), 3.10-3.03 (m, 1H), 2.81- 2.63 (m, 2H), 2.20 (t,J = 7.6 Hz, 2H), 2.14 (s, 3H), 1.98-1.84 (m, 2H), 1.46- 1.38 (m, 2H),1.20 (sxt, J = 7.3 Hz, 2H), 0.77 (t, J = 7.3 Hz, 3H) (2 exchangeableprotons not observed) 1.10 A 548.2 A 029

6-butyl-3-((4-(2-fluoro- 3-methylpyridin-4- yl)phenyl)sulfonyl)-5-((3-methoxyphenyl)(meth- yl)amino)pyridine-2,4- diol ¹H NMR (500 MHz,DMSO-d₆) δ 8.13 (d, J = 4.8 Hz, 1H), 8.02 (d, J = 7.7 Hz, 2H), 7.55 (d,J = 7.2 Hz, 2H), 7.27 (d, J = 4.8 Hz, 1H), 6.97 (t, J = 8.1 Hz, 1H),6.18 (d, J = 7.0 Hz, 1H), 6.09 (d, J = 7.6 Hz, 1H), 5.99 (br. s., 1H),3.17 (br. s., 3H), 2.99 (br. s., 3H), 2.16 (s, 5H), 1.40 (d, J = 6.2 Hz,2H), 1.22-1.16 (m, 2H), 0.77 (t, J = 7.2 Hz, 3H) (2 exchangeable protonsnot observed) 1.10 A 552.2 A 030

6-butyl-3-((4-(6-fluoro- 2-methylpyridin-3- yl)phenyl)sulfonyl)-5-((3-methoxyphenyl)(meth yl)amino)pyridine-2,4- diol ¹H NMR (500 MHz,DMSO-d₆) δ 8.09 (d, J = 8.0 Hz, 2H), 7.88 (t, J = 8.1 Hz, 1H), 7.66 (d,J = 8.0 Hz, 2H), 7.12 (d, J = 6.1 Hz, 1H), 7.06 (t, J = 8.1 Hz, 1H),6.30 (d, J = 7.6 Hz, 1H), 6.15 (d, J = 7.8 Hz, 1H), 6.07 (br. s., 1H),3.51 (br. s., 3H), 3.08 (s, 2H), 2.42-2.23 (m, 5H), 1.43 (d, J = 7.7 Hz,2H), 1.23-1.14 (m, 2H), 0.74 (t, J = 7.2 Hz, 3H) (2 exchangeable protonsnot observed) 1.10 A 552.2 B 031

6-butyl-5-((3- methoxyphenyl)(meth- yl)amino)-3-((4-(3-methylpyridin-4-yl)phen- yl)sulfonyl)pyridine- 2,4-diol ¹H NMR (500 MHz,DMSO-d₆) δ 8.52 (br. s., 1H), 8.46 (br. s., 1H), 7.97 (d, J = 7.7 Hz,2H), 7.50 (d, J = 7.6 Hz, 2H), 7.25 (d, J = 4.5 Hz, 1H), 6.95 (t, J =8.0 Hz, 1H), 6.15 (d, J = 7.1 Hz, 1H), 6.07 (d, J = 8.0 Hz, 1H), 5.97(s, 3H), 3.17 (br. s., 3H), 2.96 (s, 3H), 2.25 (s, 3H), 2.14 (br. s.,2H), 1.47-1.36 (m, 2H), 1.23-1.14 (m, 2H), 0.77 (t, J = 7.2 Hz, 3H) (2exchangeable protons not observed) 0.91 A 534.2 B 032

6-butyl-3-((4-(6-fluoro- 2-methylpyridin-3- yl)phenyl)sulfonyl)-5-((4-methoxyphenyl)(meth- yl)amino)pyridine-2,4- diol ¹H NMR (500 MHz,DMSO-d₆) δ 8.08 (d, J = 8.0 Hz, 2H), 7.88 (t, J = 8.1 Hz, 1H), 7.65 (d,J = 7.9 Hz, 2H), 7.12 (d, J = 6.4 Hz, 1H), 6.78 (d, J = 8.7 Hz, 2H),6.51 (d, J = 8.7 Hz, 2H), 3.47 (br. s., 3H), 3.05 (s, 3H), 2.38 (s, 3H),2.31 (d, J = 8.0 Hz, 2H), 1.42 (br. s., 2H), 1.26-1.16 (m, 2H), 0.76 (t,J = 7.3 Hz, 3H) (2 exchangeable protons not observed) 1.10 A 552.2 B 035

6-butyl-5-((4- methoxyphenyl)(meth- yl)amino)-3-((4-(2-methylpyridin-3-yl)phen- yl)sulfonyl)pyridine- 2,4-diol ¹H NMR (500 MHz,DMSO-d₆) δ 8.50 (d, J = 4.0 Hz, 1H), 8.04 (d, J = 8.2 Hz, 2H), 7.66 (d,J = 7.3 Hz, 1H), 7.59 (d, J = 7.9 Hz, 2H), 7.36-7.30 (m, 1H), 6.75 (d, J= 8.9 Hz, 2H), 6.47 (d, J = 8.5 Hz, 2H), 3.17 (s, 3H), 3.03 (s, 3H),2.43 (s, 3H), 2.26 (d, J = 7.9 Hz, 2H), 1.42 (dd, J = 15.6, 7.6 Hz, 2H),1.25-1.14 (m, 2H), 0.76 (t, J = 7.3 Hz, 3H) (2 exchangeable protons notobserved) 0.90 A 534.2 B 036

(S)-(6-butyl-2,4- dihydroxy-5-((4- methoxyphenyl)(meth-yl)amino)pyridin-3-yl)(3- phenylpyrrolidin-1- yl)methanone ¹H NMR (500MHz, DMSO-d₆) δ 7.32 (m, 4H), 7.24 (m, 1H), 6.76 (m, 2H), 6.48 (m, 2H),3.89 (br. s., 1H), 3.75- 3.60 (m, 6H), 3.53 (m, 1H), 3.03 (br. s., 3H),2.25 (m, 3H), 1.96 (m, 1H), 1.41 (m, 2H), 1.18 (m, 2H), 0.75 (m, 3H) (2exchangeable protons not observed) 1.05 A 476.3 B 037

6-butyl-5-((4- methoxyphenyl)(meth- yl)amino)-3-((4-(3-methylpyridin-4-yl)phen- yl)sulfonyl)pyridine- 2,4-diol ¹H NMR (500 MHz,DMSO-d₆) δ 8.55 (s, 1H), 8.49 (d, J = 4.4 Hz, 1H), 8.08 (d, J = 7.9 Hz,2H), 7.64 (d, J = 7.7 Hz, 2H), 7.29 (d, J = 4.6 Hz, 1H), 6.77 (d, J =8.7 Hz, 2H), 6.50 (d, J = 8.6 Hz, 2H), 3.65 (s, 3H), 3.04 (s, 3H), 2.29(m, 2H), 2.26 (s, 3H), 1.42 (m, 2H), 1.25-1.15 (m, 2H), 0.76 (t, J = 7.2Hz, 3H) (2 exchangeable protons not observed) 0.91 A 534.2 A 038

6-butyl-3-((4-(2-fluoro- 3-methylpyridin-4- yl)phenyl)sulfonyl)-5-((4-methoxyphenyl)(meth- yl)amino)pyridine-2,4- diol ¹H NMR (500 MHz,DMSO-d₆) δ 8.14 (d, J = 4.9 Hz, 1H), 8.11 (d, J = 8.2 Hz, 2H), 7.67 (d,J = 8.1 Hz, 2H), 7.29 (d, J = 4.9 Hz, 1H), 6.78 (d, J = 8.8 Hz, 2H),6.51 (d, J = 8.8 Hz, 2H), 3.17 (s, 3H), 3.05 (s, 3H), 2.30 (br. s., 2H),2.16 (s, 3H), 1.42 (dd, J = 13.5, 6.6 Hz, 2H), 1.25- 1.15 (m, 2H), 0.76(t, J = 7.3 Hz, 3H) (2 exchangeable protons not observed) 1.09 A 552.2 A039

6-butyl-5-((3- methoxyphenyl)(meth- yl)amino)-3-((4-(2-methylpyridin-3-yl)phen- yl)sulfonyl)pyridine- 2,4-diol ¹H NMR (500 MHz,DMSO-d₆) δ 8.51 (d, J = 4.4 Hz, 1H), 8.08 (d, J = 8.1 Hz, 2H), 7.71-7.61(m, 3H), 7.35 (dd, J = 7.4, 4.9 Hz, 1H), 7.05 (t, J = 8.1 Hz, 1H), 6.28(d, J = 7.7 Hz, 1H), 6.15 (d, J = 8.2 Hz, 1H), 6.08 (br. s., 1H), 3.68(s, 3H), 3.08 (s, 3H), 2.44 (s, 3H), 2.34- 2.24 (m, 2H), 1.50-1.37 (m,2H), 1.27- 1.15 (m, 2H), 0.76 (t, J = 7.3 Hz, 3H) (2 exchangeableprotons not observed) 0.91 A 534.2 A 040

6-butyl-5-(4-methyl- 3,4-dihydroquinolin- 1(2H)-yl)-3-((4-(3-methylpyridin-4-yl)phen- yl)sulfonyl)pyridine- 2,4-diol ¹H NMR (500 MHz,DMSO-d₆) δ 8.61- 8.38 (m, 3H), 7.99 (d, J = 7.9 Hz, 2H), 7.51 (d, J =7.3 Hz, 2H), 7.25 (d, J = 4.6 Hz, 1H), 6.66 (br. s., 1H), 6.56 (d, J =7.9 Hz, 1H), 5.97 (d, J = 7.9 Hz, 1H), 3.52 (br. s., 1H), 2.76-2.60 (m,2H), 2.29- 2.15 (m, 5H), 2.09 (s, 3H), 1.98-1.81 (m, 2H), 1.43 (br. s.,2H), 1.28-1.18 (m, 2H), 0.78 (t, J = 7.2 Hz, 3H) (2 exchangeable protonsnot observed) 1.06 A 544.3 B 042

6-butyl-5-(4-methyl- 3,4-dihydroquinolin- 1(2H)-yl)-3-((4-(2-methylpyridin-3- yl)phenyl)sulfonyl)pyridine- 2,4-diol ¹H NMR (500 MHz,DMSO-d₆) δ 8.50 (dd, J = 16.7, 4.1 Hz, 1H), 8.09 (d, J = 8.1 Hz, 1H),7.96 (d, J = 7.9 Hz, 1H), 7.67 (d, J = 7.6 Hz, 2H), 7.48 (d, J = 7.8 Hz,1H), 7.35 (d, J = 5.7 Hz, 2H), 6.76 (br. s., 1H), 6.69 (d, J = 7.8 Hz,1H), 6.05 (d, J = 8.2 Hz, 1H), 2.83-2.61 (m, 2H), 2.46- 2.40 (m, 3H),2.38-2.29 (m, 2H), 2.12 (s, 3H), 2.04-1.91 (m, 2H), 1.52-1.39 (m, 2H),1.28-1.18 (m, 3H), 0.77 (t, J = 7.3 Hz, 3H) (2 exchangeable protons notobserved) 1.05 A 544.3 B 044

6-butyl-3-((4-(2-fluoro- 3-methylpyridin-4- yl)phenyl)sulfonyl)-5-(4-methyl-3,4- dihydroquinolin-1(2H)- yl)pyridine-2,4-diol ¹H NMR (500MHz, DMSO-d₆) δ 8.16 (d, J = 5.0 Hz, 1H), 8.12 (d, J = 7.7 Hz, 2H), 7.68(d, J = 7.2 Hz, 2H), 7.31 (d, J = 5.0 Hz, 1H), 6.76 (s, 1H), 6.68 (d, J= 8.0 Hz, 1H), 6.05 (d, J = 8.0 Hz, 1H), 5.76 (s, 1H), 3.51 (t, J = 8.9Hz, 1H), 2.82-2.70 (m, 2H), 2.39-2.31 (m, 2H), 2.17 (s, 3H), 2.13 (s,3H), 2.04-1.87 (m, 2H), 1.49-1.41 (m, 2H), 1.30-1.20 (m, 2H), 0.78 (t, J= 7.3 Hz, 3H) (2 exchangeable protons were not observed) 1.26 A 562.3 A045

(6-butyl-2,4-dihydroxy- 5-(4-methyl-3,4- dihydroquinolin-1(2H)-yl)pyridin-3-yl)((S)-3- phenylpyrrolidin-1- yl)methanone ¹H NMR (500MHz, DMSO-d₆) δ 7.40- 7.18 (m, 6H), 6.71 (m, 2H), 6.06-5.91 (m, 1H),3.59-3.47 (m, 1H), 3.35-3.06 (m, 2H), 2.82-2.61 (m, 2H), 2.27 (m, 3H),2.10 (br. s., 3H), 2.03-1.94 (m, 2H), 1.90 (m, 3H), 1.44 (m, 2H), 1.23(m, 3H), 0.78 (m, 3H) (2 exchangeable protons not observed) 1.24 A 486.4A 046

6-butyl-5-(2-methyl- 3,4-dihydroquinolin- 1(2H)-yl)-3-((4-(2-methylpyridin-3-yl)phen- yl)sulfonyl)pyridine- 2,4-diol ¹H NMR (500 MHz,DMSO-d₆) δ 8.68 (br. s., 1H), 8.14 (d, J = 8.2 Hz, 2H), 7.95 (d, J = 7.2Hz, 1H), 7.73 (d, J = 8.1 Hz, 2H), 7.57 (br. s., 1H), 6.99 (d, J = 7.0Hz, 1H), 6.90 (t, J = 7.5 Hz, 1H), 6.59 (t, J = 7.2 Hz, 1H), 6.16 (d, J= 8.1 Hz, 1H), 2.94-2.70 (m, 3H), 2.48-2.45 (s, 3H), 2.39-2.26 (m, 2H),2.02 (br. s., 1H), 1.76 (br. s., 1H), 1.47 (d, J = 7.6 Hz, 2H), 1.20(dt, J = 15.0, 7.6 Hz, 2H), 1.05 (d, J = 6.4 Hz, 3H), 0.74 (t, J = 7.4Hz, 3H) (2 exchangeable protons were not observed) 1.04 A 544.3 A 047

6-butyl-3-((4-(2-fluoro- 3-methylpyridin-4- yl)phenyl)sulfonyl)-5-(2-methyl-3,4- dihdyroquinolin-1(2H)- yl)pyridine-2,4-diol ¹H NMR (500MHz, DMSO-d₆) δ 8.10 (d, J = 4.7 Hz, 1H), 7.99-7.92 (m, 2H), 7.48 (d, J= 8.1 Hz, 2H), 7.27-7.19 (m, 1H), 6.86-6.80 (m, 1H), 6.77-6.68 (m, 1H),6.39 (t, J = 7.1 Hz, 1H), 6.06 (d, J = 8.1 Hz, 1H), 3.51 (m, 3H),2.82-2.62 (m, 2H), 2.21 (m, 1H), 2.14 (s, 3H), 1.63 (m, 1H), 1.52-1.34(m, 2H), 1.23- 1.13 (m, 2H), 0.96-0.90 (m, 3H), 0.78- 0.69 (m, 3H) (2exchangeable protons were not observed) 1.25 A 562.3 A 048

6-butyl-3-((4-(6-fluoro- 2-methylpyridin-3- yl)phenyl)sulfonyl)-5-(2-methyl-3,4- dihdyroquinolin-1(2H)- yl)pyridine-2,4-diol ¹H NMR (500MHz, DMSO-d₆) δ 8.16- 8.06 (m, 2H), 7.90 (t, J = 8.0 Hz, 1H), 7.69 (d, J= 7.7 Hz, 2H), 7.13 (d, J = 6.9 Hz, 1H), 6.98 (d, J = 6.7 Hz, 1H), 6.89(br. s., 1H), 6.62-6.51 (m, 1H), 6.19- 6.07 (m, 1H), 3.67 (d, J = 10.8Hz, 1H), 2.81 (d, J = 19.2 Hz, 2H), 2.39 (s, 3H), 2.35-2.26 (m, 1H),2.02 (m, 1H), 1.76 (m, 1H), 1.47 (m, 2H), 1.27-1.14 (m, 3H), 1.04 (d, J= 6.1 Hz, 3H), 0.78-0.68 (m, 3H) (2 exchangeable protons were notobserved) 1.25 A 562.3 A 049

6-(cyclopropylmethyl)- 5-(ethyl(phenyl)amino)- 3-((4-(2-fluoro-3-methylpyridin-4- yl)phenyl)sulfonyl)pyridine- 2,4-diol ¹H NMR (500 MHz,DMSO-d₆) δ 8.02- 7.91 (m, 3H), 7.50 (br. s., 2H), 7.15 (d, J = 4.4 Hz,1H), 6.98 (br. s., 2H), 6.49 (br. s., 1H), 6.41 (d, J = 7.3 Hz, 2H),3.03 (br. s., 3H), 2.15-1.98 (m, 4H), 1.02- 0.93 (m, 3H), 0.74 (br. s,1H), 0.21 (br. s., 1H), 0.14 (br. s., 1H), 0.00 (br. s., 1H), −0.16 (br.s., 1H) (2 exchangeable protons were not observed) 1.13 A 534.3 A 050

6-(cyclopropylmethyl)- 5-(ethyl(phenyl)amino)- 3-((4-(2-methylpyridin-3-yl)phenyl)sulfonyl)pyridine- 2,4-diol ¹H NMR (500 MHz, DMSO-d₆) δ 8.35(d, J = 4.1 Hz, 1H), 7.88 (d, J = 7.7 Hz, 2H), 7.52 (d, J = 7.3 Hz, 1H),7.41 (d, J = 7.3 Hz, 2H), 7.25-7.18 (m, 1H), 6.95 (t, J = 7.4 Hz, 2H),6.48-6.41 (m, 1H), 6.38 (d, J = 7.9 Hz, 2H), 3.05 (s, 2H), 2.30 (s, 3H),2.12-1.95 (m, 2H), 0.94 (t, J = 6.9 Hz, 3H), 0.74 (br. s., 1H), 0.21(br. s., 1H), 0.16 (br. s., 1H), 0.00 (br. s., 1H), −0.14 (d, J = 4.7Hz, 1H) (2 exchangeable protons were not observed) 0.91 A 516.3 A 051

6-(cyclopropylmethyl)- 5-(ethyl(phenyl)amino)- 3-((4-(6-fluoro-2-methylpyridin-3- yl)phenyl)sulfonyl)pyridine- 2,4-diol ¹H NMR (500 MHz,DMSO-d₆) δ 7.90 (d, J = 7.3 Hz, 2H), 7.73 (t, J = 7.9 Hz, 1H), 7.46 (br.s., 2H), 6.97 (d, J = 6.9 Hz, 3H), 6.46 (d, J = 12.5 Hz, 1H), 6.40 (d, J= 7.2 Hz, 2H), 3.03 (d, J = 3.4 Hz, 2H), 2.24 (s, 3H), 2.13-1.98 (m,2H), 0.96 (br. s., 3H), 0.78-0.70 (m, 1H), 0.20 (br. s., 1H), 0.14 (br.s., 1H), 0.00 (br. s., 1H), −0.15 (br. s., 1H) (2 exchangeable protonswere not observed) 1.16 A 534.3 A 052

6-(cyclopropylmethyl)- 5-(ethyl(phenyl)amino)- 3-((4-(3-methylpyridin-4-yl)phenyl)sulfonyl)pyridine- 2,4-diol ¹H NMR (500 MHz, DMSO-d₆) δ 8.39(s, 1H), 8.34 (d, J = 4.0 Hz, 1H), 7.89 (d, J = 7.3 Hz, 2H), 7.42 (d, J= 6.8 Hz, 2H), 7.14 (d, J = 4.4 Hz, 1H), 6.94 (t, J = 7.1 Hz, 2H), 6.44(d, J = 7.4 Hz, 1H), 6.38 (d, J = 7.6 Hz, 2H), 3.04 (d, J = 2.9 Hz, 2H),2.12 (s, 3H), 2.10-1.94 (m, 2H), 0.94 (t, J = 6.8 Hz, 3H), 0.75 (br. s.,1H), 0.20 (br. s., 1H), 0.15 (br. s., 1H), 0.00 (br. s., 1H), −0.14 (d,J = 4.1 Hz, 1H) (2 exchangeable protons were not observed) 0.92 A 516.3A 053

(6-(cyclopropylmethyl)- 5-(ethyl(phenyl)amino)- 2,4-dihydroxypyridin-3-yl)(3-(3,5- difluoropyridin-2- yl)pyrrolidin-1- yl)methanone ¹H NMR (500MHz, DMSO-d₆) δ 8.36- 8.21 (m, 1H), 7.69 (t, J = 8.5 Hz, 1H), 6.92 (m,2H), 6.37 (m, 3H), 3.83-3.69 (m, 3H), 3.61-3.37 (m, 2H), 3.29 (m, 2H),3.20-3.02 (m, 1H), 2.04 (m, 3H), 1.07-0.87 (m, 3H), 0.74 (m, 1H), 0.29-0.11 (m, 2H), 0.00 (m, 1H), −0.13 (m, 1H) (2-exchangeable protons werenot observed) 1.09 A 495.3 B 054

4′-((6-butyl-5-(3,4- dihydroquinolin-1(2H)-yl)-2,4- dihydroxypyridin-3-yl)sulfonyl)-N,N- dimethyl-[1,1′- biphenyl]-2- carboxamide ¹H NMR (500MHz, DMSO-d₆) δ 8.04 (d, J = 8.0 Hz, 2H), 7.61-7.48 (m, 5H), 7.39 (d, J= 7.2 Hz, 1H), 6.94 (d, J = 7.1 Hz, 1H), 6.87 (t, J = 7.6 Hz, 1H), 6.54(t, J = 7.1 Hz, 1H), 6.14 (d, J = 8.2 Hz, 1H), 3.35 (m, 2H), 2.80-2.70(m, 2H), 2.55 (s, 6H), 2.35 (m, 2H), 1.95 (m, 2H), 1.48-1.40 (m, 2H),1.23-1.17 (m, 2H), 0.76 (t, J = 7.2 Hz, 3H) (2 exchangeable protons werenot observed) 1.18 A 586.3 B 055

4′-((6- (cyclopropylmethyl)-5- (ethyl(phenyl)amino)-2,4-dihydroxypyridin-3- yl)sulfonyl)-N-methyl- [1,1′-biphenyl]-2-carboxamide ¹H NMR (500 MHz, DMSO-d₆) δ 8.03 (d, J = 4.5 Hz, 1H),7.84-7.76 (m, 2H), 7.44-7.39 (m, 1H), 7.36-7.27 (m, 5H), 6.93 (t, J =7.6 Hz, 2H), 6.42 (t, J = 6.9 Hz, 1H), 6.36 (d, J = 8.0 Hz, 2H), 3.33-3.16 (m, 2H), 2.47 (d, J = 4.5 Hz, 3H), 2.06-1.92 (m, 2H), 0.93 (t, J =7.0 Hz, 3H), 0.74 (m, 1H), 0.27-0.16 (m, 2H), 0.00 (m, 1H), −0.11 (m,1H) (2 exchangeable protons were not observed) 1.15 A 558.3 A 056

4′-((5- (ethyl(phenyl)amino)- 2,4-dihydroxy-6-(1- methyl-1H-pyrazol-3-yl)pyridin-3- yl)sulfonyl)-N-methyl- [1,1′-biphenyl]-2- carboxamide ¹HNMR (500 MHz, DMSO-d₆) δ 8.21 (br. s., 1H), 8.01 (d, J = 7.5 Hz, 2H),7.72 (br. s., 1H), 7.55 (d, J = 7.3 Hz, 3H), 7.50- 7.39 (m, 3H), 7.13(d, J = 7.0 Hz, 2H), 6.68-6.59 (m, 3H), 6.29 (br. s., 1H), 3.88 (s, 3H),3.44-3.31 (m, 2H), 2.60 (d, J = 4.4 Hz, 3H), 1.01 (t, J = 7.1 Hz, 3H) (2exchangeable protons were not observed) 1.07 A 584 A 057

4′-((6-butyl-5-(3,4- dihydroquinolin-1(2H)-yl)-2,4- dihydroxypyridin-3-yl)sulfonyl)-[1,1′- biphenyl]-2- carboxamide ¹H NMR (500 MHz, DMSO-d₆) δ7.92 (d, J = 7.7 Hz, 2H), 7.78 (br. s., 1H), 7.53- 7.42 (m, 5H), 7.38(d, J = 7.5 Hz, 1H), 7.33 (br. s., 1H), 6.85 (d, J = 7.2 Hz, 1H), 6.77(t, J = 7.5 Hz, 1H), 6.41 (t, J = 7.1 Hz, 1H), 6.06 (d, J = 8.1 Hz, 1H),3.51 (t, J = 9.4 Hz, 1H), 3.06 (br. s., 1H), 2.80- 2.62 (m, 2H), 2.19(br. s., 2H), 1.94- 1.82 (m, 2H), 1.40 (d, J = 6.8 Hz, 2H), 1.21-1.15(m, 2H), 0.76 (t, J = 7.2 Hz, 3H) (2 exchangeable protons were notobserved) 1.17 A 558.3 A 058

5-(ethyl(phenyl)amino)- 6-(1-methyl-1H- pyrazol-3-yl)-3-((4-(2-methylpyridin-3- yl)phenyl)sulfonyl)pyridine- 2,4-diol ¹H NMR (500 MHz,DMSO-d₆) δ 8.46 (d, J = 3.6 Hz, 1H), 7.94 (d, J = 8.1 Hz, 2H), 7.65-7.58(m, 2H), 7.44 (d, J = 8.1 Hz, 2H), 7.37-7.29 (m, 1H), 7.02 (t, J = 7.7Hz, 2H), 6.58-6.44 (m, 3H), 6.21 (d, J = 1.8 Hz, 1H), 3.89 (s, 3H), 3.37(q, J = 7.0 Hz, 2H), 2.40 (s, 3H), 0.91 (t, J = 7.2 Hz, 3H) (2exchangeable protons were not observed) 0.90 A 542.3 A 059

5-(ethyl(phenyl)amino)- 3-((4-(6-fluoro-2- methylpyridin-3-yl)phenyl)sulfonyl)-6- (1-methyl-1H-pyrazol- 3-yl)pyridine-2,4-diol ¹HNMR (500 MHz, DMSO-d₆) δ 7.94 (d, J = 7.8 Hz, 2H), 7.80 (t, J = 8.2 Hz,1H), 7.60 (s, 1H), 7.44 (d, J = 7.9 Hz, 2H), 7.10-6.98 (m, 3H),6.56-6.45 (m, 3H), 6.20 (s, 1H), 3.82 (s, 3H), 3.36 (q, J = 7.2 Hz, 2H),2.34 (s, 3H), 0.90 (t, J = 7.1 Hz, 3H) (2 exchangeable protons were notobserved) 1.21 A 560.2 A 060

4′-((5- (ethyl(phenyl)amino)- 2,4-dihydroxy-6-(1- methyl-1H-pyrazol-3-yl)pyridin-3- yl)sulfonyl)-N,N- dimethyl-[1,1′- biphenyl]-2- carboxamide¹H NMR (500 MHz, DMSO-d₆) δ 7.88 (d, J = 8.0 Hz, 2H), 7.61 (s, 1H), 7.51(d, J = 7.7 Hz, 1H), 7.48-7.42 (m, 2H), 7.39 (d, J = 8.1 Hz, 2H), 7.33(d, J = 7.2 Hz, 1H), 7.02 (t, J = 7.6 Hz, 2H), 6.56-6.46 (m, 3H), 6.20(s, 1H), 3.84 (s, 3H), 3.36 (d, J = 5.4 Hz, 2H), 2.72 (s, 3H), 2.40 (br.s., 3H), 0.91 (t, J = 7.1 Hz, 3H) (2 exchangeable protons were notobserved) 1,14 A 598.3 A 061

4′-((6-butyl-5-(3,4- dihydroquinolin-1(2H)-yl)-2,4- dihydroxypyridin-3-yl)sulfonyl)-N-methyl- [1,1′-biphenyl]-2- carboxamide ¹H NMR (500 MHz,DMSO-d₆) δ 8.14 (d, J = 4.5 Hz, 1H), 7.96-7.86 (m, 3H), 7.54-7.48 (m,1H), 7.46-7.36 (m, 4H), 6.83 (d, J = 7.1 Hz, 1H), 6.75 (t, J = 7.4 Hz,1H), 6.39 (t, J = 6.9 Hz, 1H), 6.04 (d, J = 8.1 Hz, 1H), 3.50 (m, 2H),2.78-2.62 (m, 2H), 2.57 (d, J = 4.5 Hz, 3H), 2.17 (m, 2H), 1.86 (m, 2H),1.39 (m, 2H), 1.20-1.13 (m, 2H), 0.75 (t, J= 7.2 Hz, 3H) (2 exchangeableprotons were not observed) 1.17 A 572.3 A 062

4′-((6- (cyclopropylmethyl)-5- (ethyl(phenyl)amino)-2,4-dihydroxypyridin-3- yl)sulfonyl)-N,N- dimethyl-[1,1′- biphenyl]-2-carboxamide ¹H NMR (500 MHz, DMSO-d₆) δ 7.79 (d, J = 7.9 Hz, 2H),7.44-7.39 (m, 1H), 7.38-7.33 (m, 2H), 7.30 (d, J = 7.9 Hz, 2H), 7.23 (d,J = 7.0 Hz, 1H), 6.92 (t, J = 7.6 Hz, 2H), 6.40 (t, J = 7.0 Hz, 1H),6.35 (d, J = 7.9 Hz, 2H), 3.31-3.15 (m, 2H), 2.44 (s, 6H), 2.05-1.92 (m,2H), 0.93 (t, J = 7.0 Hz, 3H), 0.74 (m, 1H), 0.26-0.13 (m, 2H), 0.01 (m,1H), −0.11 (m, 1H) (2 exchangeable protons were not observed) 1.20 A572.3 A 063

5-(ethyl(phenyl)amino)- 3-((4-(2-fluoro-3- methylpyridin-4-yl)phenyl)sulfonyl)-6- (1-methyl-1H-pyrazol- 3-yl)pyridine-2,4-diol ¹HNMR (500 MHz, DMSO-d₆) δ 8.10 (d, J = 4.9 Hz, 1H), 7.97 (d, J = 8.2 Hz,2H), 7.62 (s, 1H), 7.48 (d, J = 7.9 Hz, 2H), 7.23 (d, J = 4.9 Hz, 1H),7.03 (t, J = 7.5 Hz, 2H), 6.56-6.46 (m, 3H), 6.22 (s, 1H), 3.85 (s, 3H),3.37 (d, J = 5.8 Hz, 2H), 2.14 (s, 3H), 0.92 (t, J = 7.0 Hz, 3H) (2exchangeable protons were not observed) 1.17 A 560.3 A 064

5-(ethyl(phenyl)amino)- 6-(1-methyl-1H- pyrazol-3-yl)-3-((4-(3-methylpyridin-4- yl)phenyl)sulfonyl)pyri- dine-2,4-diol ¹H NMR (500 MHz,DMSO-d₆) δ 8.51 (br. s., 1H), 8.45 (br. s., 1H), 7.96 (d, J = 8.2 Hz,2H), 7.63 (s, 1H), 7.47 (d, J = 7.9 Hz, 2H), 7.24 (d, J = 4.9 Hz, 1H),7.08-6.98 (m, 2H), 6.57-6.47 (m, 3H), 6.22 (s, 1H), 3.90 (s, 3H), 3.38(d, J = 6.7 Hz, 2H), 2.24 (s, 3H), 0.93 (t, J = 7.2 Hz, 3H) (2exchangeable protons were not observed) 0.92 A 542.3 A 065

4′-((6-butyl-2,4- dihydroxy-5-(meth- yl(phenyl)amino)pyridin-3-yl)sulfonyl)- [1,1′-biphenyl]-2- carboxamide ¹H NMR (500 MHz, DMSO-d₆)δ 7.98- 7.88 (m, 2H), 7.74 (br. s., 1H), 7.55- 7.41 (m, 5H), 7.39 (d, J= 7.3 Hz, 1H), 7.31 (br. s., 1H), 7.11-7.02 (m, 2H), 6.55 (t, J = 6.9Hz, 1H), 6.47 (d, J = 7.9 Hz, 2H), 2.98 (s, 3H), 2.14 (d, J = 7.3 Hz,2H), 1.40 (br. s., 2H), 1.21-1.14 (m, 2H), 0.75 (t, J = 7.3 Hz, 3H) (2exchangeable protons were not observed) 1.16 A 532.3 A 066

(R)-(6-butyl-5- (ethyl(phenyl)amino)- 2,4-dihydroxypyridin-3-yl)(3-phenylpyrrolidin- 1-yl)methanone ¹H NMR (500 MHz, DMSO-d₆) δ 7.32(br. s., 4H), 7.24 (t, J = 4.6 Hz, 1H), 7.13 (br. s., 2H), 6.64 (br. s.,1H), 6.55 (d, J = 8.2 Hz, 2H), 4.04-3.15 (m, 6H), 2.26 (br. s., 4H),1.98 (br. s., 1H), 1.41 (br. s., 2H), 1.20-1.07 (m, 5H), 0.72 (br. s.,3H) (2 exchangeable protons were not observed) 0.975 A 460.2 B 067

(6-butyl-5- (ethyl(phenyl)amino)- 2,4-dihydroxypyridin-3-yl(3-(5-chloropyridin- 2-yl)pyrrolidin-1- yl)methanone ¹H NMR (500 MHz,DMSO-d₆) δ 8.56 (br. s., 1H), 7.88 (d, J = 6.3 Hz, 1H), 7.44 (br. s.,1H), 7.11 (br. s., 2H), 6.72-6.48 (m, 3H), 3.96-3.14 (m, 4H), 2.40-2.00(m, 6H), 1.40 (br. s., 3H), 1.19-1.06 (m, 5H), 0.71 (t, J = 6.8 Hz, 3H)(2 exchangeable protons were not observed) 0.925 A 495.2 A 068

(S)-(6-butyl-2,4- dihydroxy-5-(phen- yl(propyl)a- mino)pyridin-3-yl)(3-phenylpyrrolidin-1- yl)methanone ¹H NMR (500 MHz, DMSO-d₆) δ 7.33 (br.s., 4H), 7.16-7.05 (m, 3H), 6.71- 6.61 (m, 1H), 6.54 (d, J = 8.2 Hz,2H), 3.94-3.62 (m, 2H), 3.60-3.29 (m, 1H), 2.50-2.38 (m, 2H), 2.35-2.19(m, 4H), 2.17-1.90 (m, 2H), 1.61-1.50 (m, 2H), 1.41 (br. s., 2H), 1.15(br. s., 2H), 0.89 (d, J = 6.7 Hz, 3H), 0.71 (br. s., 3H) (2exchangeable protons were not observed) 1.03 A 474.2 B 069

(R)-(6-butyl-2,4- dihydroxy-5- (phenyl(propyl)a- mino)pyridin-3-yl)(3-phenylpyrrolidin-1- yl)methanone ¹H NMR (500 MHz, DMSO-d₆) δ 7.39- 7.21(m, 5H), 7.13 (br. s., 2H), 6.71- 6.61 (m, 1H), 6.54 (d, J = 8.0 Hz,2H), 3.96-3.26 (m, 4H), 2.26 (br. s., 5H), 1.62-1.50 (m, 2H), 1.41 (br.s., 2H), 1.26-1.09 (m, 4H), 0.89 (d, J = 6.7 Hz, 3H), 0.71 (br. s., 3H)(2 exchangeable protons were not observed) 1.03 A 474.2 B 070

(6-butyl-5- (ethyl(phenyl)amino)- 2,4-dihydroxypyridin-3-yl)(3-(5-chloro-3- fluoropyridin-2- yl)pyrrolidin-1- yl)methanone ¹H NMR(500 MHz, DMSO-d₆) δ 8.49 (br. s., 1H), 8.07 (br. s., 1H), 7.13 (br. s.,2H), 6.65 (br. s., 1H), 6.54 (br. s., 2H), 3.91-3.28 (m, 4H), 2.50-2.46(m, 2H), 2.26 (d, J = 7.2 Hz, 4H), 2.12 (br. s., 1H), 1.40 (br. s., 2H),1.23-1.04 (m, 5H), 0.71 (br. s., 3H) (2 exchangeable protons were notobserved) 0.979 A 513.1 A 071

(6-butyl-5- (ethyl(phenyl)amino)- 2,4-dihydroxypyridin-3- yl)(3-(3,5-difluoropyridin-2- yl)pyrrolidin-1- yl)methanone ¹H NMR (500 MHz,DMSO-d₆) δ 8.48 (br. s., 1H), 7.92 (br. s., 1H), 7.33-7.00 (m, 2H),6.74-6.46 (m, 3H), 4.04-3.28 (m, 5H), 2.40-2.02 (m, 5H), 1.40 (br. s.,3H), 1.19-1.06 (m, 5H), 0.71 (br. s., 3H) (2 exchangeable protons werenot observed) 0.955 A 497.2 A 072

(6-butyl-5- (ethyl(phenyl)amino)- 2,4-dihydroxypyridin-3-yl)(3-(5-chloro-3- fluoropyridin-2- yl)pyrrolidin-1- yl)methanone ¹H NMR(500 MHz, DMSO-d₆) δ 8.49 (br. s., 1H), 8.06 (br. s., 1H), 7.13 (br. s.,2H), 6.65 (br. s., 1H), 6.55 (br. s., 2H), 3.91-3.28 (m, 4H), 2.50-2.44(m, 2H), 2.26 (d, J = 7.2 Hz, 4H), 2.12 (br. s., 1H), 1.40 (br. s., 2H),1.21-1.04 (m, 5H), 0.71 (br. s., 3H) (2 exchangeable protons were notobserved) 1.00 A 513.2 A 073

(6-butyl-5- (ethyl(phenyl)amino)- 2,4-dihydroxypyridin-3- yl)(3-(3,5-difluoropyridin-2- yl)pyrrolidin-1- yl)methanone ¹H NMR (500 MHz,DMSO-d₆) δ 8.48 (br. s., 1H), 7.92 (br. s., 1H), 7.26-7.06 (m, 2H),6.66-6.56 (m, 3H), 3.77-3.69 (m, 5H), 2.40-2.02 (m, 5H), 1.40 (br. s.,3H), 1.40-1.10 (m, 5H), 0.71 (br. s., 3H) (2 exchangeable protons werenot observed) 0.958 A 497.2 A 074

(6-butyl-5- (ethyl(phenyl)amino)- 2,4-dihydroxypyridin-3- yl)(4-(2,3-di-chlorobenzyl)piperazin- 1-yl)methanone ¹H NMR (500 MHz, DMSO-d₆) δ 7.69(d, J = 7.9 Hz, 1H), 7.60 (d, J = 7.3 Hz, 1H), 7.45 (t, J = 7.8 Hz, 1H),7.14 (t, J = 7.7 Hz, 2H), 6.66 (t, J = 7.1 Hz, 1H), 6.54 (d, J = 8.1 Hz,2H), 3.66-3.34 (m, 4H), 3.06-2.86 (m, 2H), 2.55 (s, 4H), 2.20 (br. s.,2H), 1.56-1.22 (m, 3H), 1.19-1.04 (m, 6H), 0.68 (t, J = 7.3 Hz, 3H) (2exchangeable protons were not observed) 0.908 A 557.2 B 075

(6-butyl-5- (ethyl(phenyl)amino)- 2,4-dihydroxypyridin-3- yl)(3-(2-fluorophenyl)pyrrolidin- 1-yl)methanone ¹H NMR (500 MHz, DMSO-d₆) δ .48-7.40 (m, 1H), 7.36-7.28 (m, 1H), 7.22- 7.10 (m, 4H), 6.70-6.62 (m, 1H),6.55 (d, J = 8.0 Hz, 2H), 4.02-3.37 (m, 5H), 2.26 (br. s., 5H), 1.41 (br. s, 3H), 1.19- 1.07 (m, 5H), 0.71 (br. s., 3H) (2 exchangeableprotons were not observed) 1.23 A 478.9 A 076

(6-butyl-5- (ethyl(phenyl)amino)- 2,4-dihydroxypyridin-3-yl)(3-(5-chloropyridin- 2-yl)pyrrolidin-1- yl)methanone ¹H NMR (500 MHz,DMSO-d₆) δ 8.56 (br. s., 1H), 7.88 (d, J = 6.3 Hz, 1H), 7.44 (br. s.,1H), 7.10 (br. s., 2H), 6.73-6.44 (m, 3H), 3.98-3.34 (m, 2H), 2.55 (s,2H), 2.34-2.16 (m, 3H), 2.08 (s, 1H), 1.91 (s, 2H), 1.41 (br. s., 2H),1.15 (d, J = 6.5 Hz, 3H), 1.09 (d, J = 6.2 Hz, 3H), 0.72 (t, J = 6.9 Hz,3H) (2 exchangeable protons were not observed) 0.956 A 495.2 B 077

3-((4- bromophenyl)sulfonyl)- 6-butyl-5-(ethyl(phen- yl)amino)pyridine-2,4-diol ¹H NMR (500 MHz, CHLOROFORM- d) δ 11.53 (s, 1H), 10.64 (br. s.,1H), 7.96 (d, J = 8.5 Hz, 2H), 7.67 (d, J = 8.5 Hz, 2H), 7.28-7.25 (m,2H), 6.85 (t, J = 7.3 Hz, 1H), 6.62 (d, J = 7.7 Hz, 2H), 2.72-2.41 (m,2H), 1.63-1.59 (m, 2H), 1.43-1.24 (m, 5H), 0.96-0.79 (m, 5H) 1.09 A505.0 B 078

6-butyl-5- (ethyl(phenyl)amino)-3- ((4-(3-methylpyridin-4-yl)phenyl)sulfonyl) pyridine-2,4-diol ¹H NMR (600 MHz, DMSO-d₆) δ 8.52(s, 1H), 8.47 (d, J = 4.6 Hz, 1H), 8.04 (d, J = 7.7 Hz, 2H), 7.58 (br.s., 2H), 7.27 (d, J = 4.8 Hz, 1H), 7.09 (br. s., 2H), 6.64- 6.55 (m,1H), 6.51 (d, J = 6.9 Hz, 2H), 3.17 (d, J = 3.4 Hz, 2H), 2.24 (s, 5H),1.44-1.34 (m, 2H), 1.16 (d, J = 7.5 Hz, 2H), 1.09 (t, J = 6.9 Hz, 3H),0.72 (t, J = 7.4 Hz, 3H) (2 exchangeable protons were not observed) 0.89A 518.2 A 079

6-butyl-5- (ethyl(phenyl)amino)-3- ((4-(2-methylpyridin-3-yl)phenyl)sulfonyl)pyri- dine-2,4-diol ¹H NMR (500 MHz, DMSO-d₆) δ 8.47(d, J = 4.0 Hz, 1H), 7.98 (d, J = 8.0 Hz, 2H), 7.63 (d, J = 7.2 Hz, 1H),7.51 (d, J = 7.9 Hz, 2H), 7.33 (dd, J = 7.4, 5.0 Hz, 1H), 7.06 (t, J =7.7 Hz, 2H), 6.55 (s, 1H), 6.47 (d, J = 8.0 Hz, 2H), 2.41 (s, 3H),2.32-2.11 (m, 2H), 1.51-1.34 (m, 2H), 1.22 (s, 2H), 1.19-1.11 (m, 2H),1.07 (t, J = 7.1 Hz, 3H), 0.71 (t, J = 7.3 Hz, 3H) (2 exchangeableprotons were not observed) 0.88 A 518.2 A 080

6-butyl-5- (ethyl(phenyl)amino)-3- ((4-(2-fluoro-3- methylpyridin-4-yl)phenyl)sulfonyl)pyri- dine-2,4-diol ¹H NMR (600 MHz, DMSO-d₆) δ 8.12(d, J = 4.8 Hz, 1H), 8.04 (br. s., 2H), 7.57 (br. s., 2H), 7.26 (d, J =4.8 Hz, 1H), 7.08 (br. s., 2H), 6.56 (d, J = 6.1 Hz, 1H), 6.50 (br. s.,2H), 3.17 (d, J = 4.4 Hz, 3H), 2.15 (s, 4H), 1.44-1.36 (m, 2H),1.19-1.13 (m, 2H), 1.11-1.02 (m, 3H), 0.72 (t, J = 7.3 Hz, 3H) (2exchangeable protons were not observed) 1.09 A 536.3 A 081

6-butyl-5- (ethyl(phenyl)amino)-3- ((4-(2-methoxypyridin-4-yl)phenyl)sulfonyl)pyri- dine-2,4-diol ¹H NMR (500 MHz, DMSO-d₆) δ 8.28(d, J = 5.3 Hz, 1H), 8.11 (d, J = 8.3 Hz, 2H), 8.01 (d, J = 8.3 Hz, 2H),7.37 (d, J = 4.5 Hz, 1H), 7.28 (s, 1H), 7.20-7.12 (m, 3H), 7.07 (s, 1H),6.68 (t, J = 7.2 Hz, 1H), 6.57 (d, J = 8.2 Hz, 2H), 3.90 (s, 3H), 3.56(br. s., 2H), 2.44-2.22 (m, 2H), 1.47-1.31 (m, 2H), 1.14 (t, J = 7.2 Hz,5H), 0.69 (s, 3H) 1.07 A 534.2 A 082

1-(4-((6-butyl-5- (ethyl(phenyl)amino)- 2,4-dihydroxypyridin-3-yl)sulfonyl)phenyl)-5- chloropyridin-2(1H)- one ¹H NMR (500 MHz,DMSO-d₆) δ 7.98 (br. s., 3H), 7.61 (d, J = 9.4 Hz, 3H), 7.10 (br. s.,2H), 6.68-6.36 (m, 4H), 3.61 (br. s., 2H), 2.40-2.07 (m, 2H), 1.98- 1.63(m, 2H), 1.37 (br. s., 2H), 1.11 (br. s., 3H), 0.69 (br. s., 3H) (2exchangeable protons were not observed) 1.05 A 554.2 A 083

4′-((6-butyl-5- (ethyl(phenyl)amino)- 2,4-dihydroxypyridin-3-yl)sulfonyl)-[1,1′- biphenyl]-2-carbonitrile ¹H NMR (500 MHz, DMSO-d₆) δ8.01 (d, J = 8.1 Hz, 2H), 7.96 (d, J = 7.7 Hz, 1H), 7.85-7.78 (m, 1H),7.69-7.58 (m, 4H), 7.03 (t, J = 7.7 Hz, 2H), 6.51 (s, 1H), 6.45 (d, J =8.0 Hz, 2H), 3.67-3.14 (m, 2H), 2.25-2.06 (m, 2H), 1.39 (d, J = 7.1 Hz,2H), 1.22-1.11 (m, 2H), 1.05 (t, J = 7.1 Hz, 3H), 0.72 (t, J = 7.3 Hz,3H) (2 exchangeable protons were not observed) 1.09 A 528.2 A 084

6-butyl-5- (ethyl(phenyl)amino)-3- (phenylsulfonyl)pyridine- 2,4-diol ¹HNMR (500 MHz, DMSO-d₆) δ 8.08- 7.72 (m, 2H), 7.53 (br. s., 3H), 7.06(br. s., 2H), 6.69-6.13 (m, 3H), 3.68-3.01 (m, 2H), 2.38-1.47 (m, 4H),1.39-0.96 (m, 5H), 0.68 (br. s., 3H (2 exchangeable protons were notobserved) 1.05 A 427.2 B 085

4′-((6-butyl-5- (ethyl(phenyl)amino)- 2,4-dihydroxypyridin-3-yl)sulfonyl)-[1,1′- biphenyl]-2- carboxamide ¹H NMR (600 MHz, DMSO-d₆) δ7.90 (d, J = 8.1 Hz, 2H), 7.74 (br. s., 1H), 7.52- 7.41 (m, 5H), 7.39(d, J = 7.7 Hz, 1H), 7.31 (br. s., 1H), 7.05 (t, J = 7.7 Hz, 2H), 6.53(t, J = 7.0 Hz, 1H), 6.47 (d, J = 8.1 Hz, 2H), 3.53 (br. s, 2H),2.25-2.09 (m, 2H), 1.40 (dd, J = 13.8, 7.0 Hz, 2H), 1.20-1.12 (m, 2H),1.07 (t, J = 7.1 Hz, 3H), 0.73 (t, J = 7.4 Hz, 3H) (2 exchangeableprotons were not observed) 0.99 A 546.2 A 086

6-butyl-5- (ethyl(phenyl)amino)-3- ((4-(6-fluoro-2- methylpyridin-3-yl)phenyl)sulfonyl) pyridine-2,4-diol ¹H NMR (500 MHz, DMSO-d₆) δ 7.97(d, J = 8.0 Hz, 2H), 7.83 (t, J = 8.2 Hz, 1H), 7.50 (d, J = 8.0 Hz, 2H),7.13-6.99 (m, 3H), 6.53 (t, J = 7.1 Hz, 1H), 6.46 (d, J = 8.2 Hz, 2H),2.36 (s, 3H), 2.16 (br. s., 2H), 1.39 (br. s., 2H), 1.22 (s, 2H), 1.18-1.09 (m, 2H), 1.06 (t, J = 7.1 Hz, 3H), 0.71 (t, J = 7.3 Hz, 3H) (2exchangeable protons were not observed) 1.10 A 536.2 A 087

6-butyl-5- (ethyl(phenyl)amino)-3- ((2′-(methoxymethyl)-[1,1′-biphenyl]-4- yl)sulfonyl)pyridine- 2,4-diol ¹H NMR (500 MHz,DMSO-d₆) δ 7.98 (d, J = 7.9 Hz, 2H), 7.51 (d, J = 6.6 Hz, 3H), 7.45-7.38(m, 2H), 7.30 (d, J = 6.1 Hz, 1H), 7.08 (t, J = 7.5 Hz, 2H), 6.58 (br.s., 1H), 6.50 (d, J = 8.0 Hz, 2H), 4.28 (s, 2H), 3.21 (s, 3H), 2.50-2.49(m, 2H), 2.20 (br. s., 2H), 1.47-1.34 (m, 2H), 1.16 (d, J = 7.3 Hz, 2H),1.09 (t, J = 7.1 Hz, 3H), 0.72 (t, J = 7.3 Hz, 3H) (2 exchangeableprotons were not observed) 1.13 A 547.3 A 088

3-([1,1′-biphenyl]-4- ylsulfonyl)-6-butyl-5- (ethyl(phenyl)amino)pyri-dine-2,4-diol ¹H NMR (500 MHz, DMSO-d₆) δ 7.99 (d, J = 8.2 Hz, 2H), 7.78(d, J = 8.2 Hz, 2H), 7.71 (d, J = 7.6 Hz, 2H), 7.50 (t, J = 7.5 Hz, 2H),7.43 (d, J = 7.3 Hz, 1H), 7.07 (t, J = 7.6 Hz, 2H), 6.60-6.54 (m, 1H),6.49 (d, J = 7.9 Hz, 2H), 3.35-3.24 (m, 2H), 2.31-2.13 (m, 2H),1.47-1.32 (m, 2H), 1.20-1.11 (m, 2H), 1.08 (t, J = 7.2 Hz, 3H), 0.71 (t,J = 7.3 Hz, 3H) (2 exchangeable protons were not observed) 1.19 A 503.2B 090

6-butyl-5-(methyl(m- tolyl)amino)-3-((4-(3- methylpyridin-4-yl)phenyl)sulfonyl)pyri- dine-2,4-diol ¹H NMR (600 MHz, DMSO-d₆) δ 8.59-8.42 (m, 2H), 8.05 (d, J = 7.9 Hz, 2H), 7.59 (d, J = 7.9 Hz, 2H), 7.27(d, J = 4.0 Hz, 1H) ,6.99 (t, J = 7.7 Hz, 1H), 6.45 (d, J = 7.1 Hz, 1H),6.37-6.26 (m, 2H), 3.03 (s, 3H), 2.25 (s, 5H), 2.19 (s, 3H), 1.47- 1.36(m, 2H), 1.24-1.12 (m, 2H), 0.75 (t, J = 7.3 Hz, 3H) (2 exchangeableprotons were not observed) 0.94 A 518.2 A 091

6-butyl-3-((4-(2-fluoro- 3-methylpyridin-4- yl)phenyl)sulfonyl)-5(methyl(m- tolyl)amino)pyridine-2,4-diol ¹H NMR (600 MHz, DMSO-d₆) δ8.12 (d, J = 4.8 Hz, 1H), 8.06 (d, J = 8.1 Hz, 2H), 7.60 (d, J = 7.9 Hz,2H), 7.26 (d, J = 4.8 Hz, 1H), 6.98 (t, J = 7.8 Hz, 1H), 6.44 (d, J =7.1 Hz, 1H), 6.36-6.28 (m, 2H), 3.02 (s, 3H), 2.22 (br. s., 2H), 2.19(s, 3H), 2.15 (s, 3H), 1.47-1.36 (m, 2H), 1.24-1.14 (m, 2H), 0.75 (t, J= 7.3 Hz, 3H) (2 exchangeable protons were not observed) 1.13 A 536.2 A092

6-butyl-3-((4-(2-fluoro- 3-methylpyridin-4- yl)phenyl)sulfonyl)-5-(methyl(p- tolyl)amino)pyridine-2,4-diol ¹H NMR (600 MHz, DMSO-d₆) δ8.02 (d, J = 5.0 Hz, 1H), 7.96 (d, J = 8.1 Hz, 2H), 7.50 (d, J = 8.1 Hz,2H), 7.16 (d, J = 4.8 Hz, 1H), 6.82 (d, J = 8.3 Hz, 2H), 6.31 (d, J =8.3 Hz, 2H), 2.91 (s, 3H), 2.19-2.09 (m, 2H), 2.04 (d, J = 3.0 Hz, 6H),1.37-1.24 (m, 2H), 1.13-1.01 (m, 2H), 0.64 (t, J = 7.4 Hz, 3H) (2exchangeable protons were not observed) 1.13 A 536.2 A 093

3-((4- bromophenyl)sulfonyl)- 6-butyl-5-(methyl(m- tolyl)amino)pyridine-2,4-diol ¹H NMR (400 MHz, CHLOROFORM- d) δ 11.52 (br. s., 1H), 10.52(br. s., 1H), 8.06-7.85 (m, 2H), 7.67 (d, J = 8.6 Hz, 2H), 7.15 (t, J =7.7 Hz, 1H), 6.67 (d, J = 7.3 Hz, 1H), 6.46-6.33 (m, 2H), 3.18 (s, 3H),2.66-2.39 (m, 2H), 2.34 (s, 3H), 1.64-1.57 (m, 2H), 1.35 (dd, J = 15.2,7.3 Hz, 2H), 0.91 (t, J = 7.4 Hz, 3H) 1.15 A 505.1 B 094

6-butyl-5-(methyl(p- tolyl)amino)-3-((4-(3- methylpyridin-4-yl)phenyl)sulfonyl)pyri- dine-2,4-diol ¹H NMR (600 MHz, DMSO-d₆) δ 8.53(br. s., 1H), 8.48 (d, J = 3.2 Hz, 1H), 8.07 (d, J = 8.1 Hz, 2H), 7.61(d, J = 7.9 Hz, 2H), 7.28 (d, J = 4.6 Hz, 1H), 6.94 (d, J = 8.3 Hz, 2H),6.44 (d, J = 8.1 Hz, 2H), 3.03 (s, 3H), 2.25 (s, 5H), 2.16 (s, 3H),1.47-1.37 (m, 2H), 1.22-1.15 (m, 2H), 0.75 (t, J = 7.3 Hz, 3H) (2exchangeable protons were not observed) 0.94 A 518.2 A 095

6-butyl-3-((4-(6-fluoro- 2-methylpyridin-3- yl)phenyl)sulfonyl)-5-(methyl(m- tolyl)amino)pyridine-2,4-diol ¹H NMR (600 MHz, DMSO-d₆) δ8.06 (d, J = 8.1 Hz, 2H), 7.86 (t, J = 8.1 Hz, 1H), 7.61 (d, J = 7.9 Hz,2H), 7.10 (d, J = 6.9 Hz, 1H), 7.01 (t, J = 7.8 Hz, 1H), 6.47 (d, J =7.3 Hz, 1H), 6.39-6.29 (m, 2H), 3.04 (s, 3H), 2.37 (s, 3H), 2.30- 2.23(m, 2H), 2.20 (s, 3H), 1.42 (t, J = 7.7 Hz, 2H), 1.23-1.13 (m, 2H), 0.75(t, J = 7.3 Hz, 3H) (2 exchangeable protons were not observed) 1.12 A536.2 B 096

6-butyl-5-(methyl(m- tolyl)amino)-3-((4-(2- methylpyridin-3-yl)phenyl)sulfonyl)pyri- dine-2,4-diol ¹H NMR (500 MHz, DMSO-d₆) δ 8.51(d, J = 4.1 Hz, 1H), 8.09 (d, J = 8.2 Hz, 2H), 7.75-7.61 (m, 3H), 7.35(dd, J = 7.4, 4.9 Hz, 1H), 7.04 (t, J = 7.8 Hz, 1H), 6.51 (d, J = 7.2Hz, 1H), 6.40 (br. s., 1H), 6.35 (d, J = 80.0 Hz, 1H), 3.08 (s, 3H),2.44 (s, 3H), 2.30 (d, J = 7.9 Hz, 2H), 2.22 (s, 3H), 1.49-1.37 (m, 2H),1.24-1.12 (m, 2H), 0.75 (t, J = 7.3 Hz, 3H) (2 exchangeable protons werenot observed) 0.93 A 518.2 A 097

6-butyl-5-(methyl(p- tolyl)amino)-3-((4-(2- methylpyridin-3-yl)phenyl)sulfonyl) pyridine-2,4-diol ¹H NMR (500 MHz, DMSO-d₆) δ 8.50(d, J = 4.2 Hz, 1H), 8.06 (d, J = 8.1 Hz, 2H), 7.79-7.56 (m, 3H), 7.35(dd, J = 7.4, 4.9 Hz, 1H), 6.95 (d, J = 8.2 Hz, 2H), 6.45 (d, J = 8.2Hz, 2H), 3.04 (s, 3H), 2.43 (s, 3H), 2.26 (br. s., 2H), 2.17 (s, 3H),1.42 (d, J = 7.3 Hz, 2H), 1.24- 1.14 (m, 2H), 0.75 (t, J = 7.3 Hz, 3H)(2 exchangeable protons were not observed) 0.94 A 518.2 B 098

1-(4-((6-butyl-2,4- dihydroxy-5-(methyl(p- tolyl)amino)pyridin-3-yl)sulfonyl)phenyl)-5- methylpyridin-2(1H)-one ¹H NMR (500 MHz, DMSO-d₆)δ 8.01 (d, J = 8.2 Hz, 2H), 7.52-7.45 (m, 3H), 7.41 (d, J = 9.5 Hz, 1H),6.88 (d, J = 7.9 Hz, 2H), 6.45 (d, J = 9.2 Hz, 1H), 6.37 (d, J = 8.2 Hz,2H), 2.96 (s, 3H), 2.14 (s, 5H), 2.05 (s, 3H), 1.40 (br. s., 2H), 1.25-1.14 (m, 2H), 0.76 (t, J = 7.3 Hz, 3H) (2 exchangeable protons were notobserved) 1.09 A 534.2 A 099

1-(4-((6-butyl-2,4- dihydroxy-5-(methyl(m- tolyl)amino)pyridin-3-yl)sulfonyl)phenyl)-5- methylpyridin-2(1H)-one ¹H NMR (500 MHz, DMSO-d₆)δ 8.14 (d, J = 8.5 Hz, 2H), 7.69 (d, J = 8.4 Hz, 2H), 7.54 (br. s., 1H),7.44 (dd, J = 9.3, 2.2 Hz, 1H), 7.09-6.91 (m, 1H), 6.59- 6.32 (m, 4H),3.09 (s, 3H), 2.37-2.27 (m, 2H), 2.23 (s, 3H), 2.06 (s, 3H), 1.51- 1.37(m, 2H), 1.25-1.11 (m, 2H), 0.75 (t, J = 7.3 Hz, 3H) (2 exchangeableprotons were not observed) 1.08 A 534.2 B 100

6-butyl-3-((4- cyclopropylphenyl)sulfo- nyl)-5-(methyl(p-tolyl)amino)pyridine- 2,4-diol ¹H NMR (500 MHz, DMSO-d₆) δ 7.74 (d, J =7.9 Hz, 2H), 7.12 (d, J = 7.9 Hz, 2H), 6.86 (d, J = 8.2 Hz, 2H), 6.34(d, J = 7.9 Hz, 2H), 2.94 (s, 3H), 2.14 (s, 5H), 2.01-1.87 (m, 1H),1.43-1.34 (m, 2H), 1.22-1.12 (m, 2H), 1.00 (d, J = 6.4 Hz, 2H),0.80-0.67 (m, 5H) (2 exchangeable protons were not observed) 1.15 A467.3 B 101

6-butyl-5-((3- fluorophenyl)(methyl)a- mino)-3-((4-(2- methylpyridin-3-yl)phenyl)sulfonyl)pyri- dine-2,4-diol ¹H NMR (500 MHz, DMSO-d₆) δ 8.44(br. s., 1H), 8.00 (d, J = 7.6 Hz, 2H), 7.64 (d, J = 7.6 Hz, 1H), 7.51(d, J = 7.6 Hz, 2H), 7.36-7.28 (m, 1H), 7.09 (d, J = 7.3 Hz, 1H),6.38-6.12 (m, 3H), 2.99 (br. s., 3H), 2.39 (s, 3H), 2.19 (d, J = 7.3 Hz,2H), 1.38 (d, J = 7.3 Hz, 2H), 1.24-1.11 (m, 2H), 0.72 (t, J = 7.0 Hz,3H) (2 exchangeable protons were not observed) 0.91 A 522.2 A 102

6-butyl-5-((3- chlorophenyl)(methyl)a- mino)-3-((4-(2- methylpyridin-3-yl)phenyl)sulfonyl)pyri- dine-2,4-diol ¹H NMR (500 MHz, DMSO-d₆) δ 8.44(br. s., 1H), 7.97 (d, J = 7.9 Hz, 2H), 7.62 (d, J = 7.0 Hz, 1H), 7.47(d, J = 7.6 Hz, 2H), 7.33 (br. s., 1H), 7.07 (t, J = 7.9 Hz, 1H), 6.56(d, J = 7.6 Hz, 1H), 6.41 (d, J = 7.9 Hz, 1H), 6.37 (br. s., 1H), 2.96(s, 3H), 2.23-2.07 (m, 2H), 1.90 (s, 3H), 1.37 (d, J = 7.0 Hz, 2H),1.20-1.10 (m, 2H), 0.72 (t, J = 7.0 Hz, 3H). (2 exchangeable protonswere not observed) 0.99 A 538.2 B 103

6-butyl-5-((4- chlorophenyl)(methyla- mino)-3-((4-(2-fluoro-3-methylpyridin-4- yl)phenyl)sulfonyl)pyri- dine-2,4-diol ¹H NMR (500 MHz,DMSO-d₆) δ 8.15 (d, J = 4.9 Hz, 1H), 8.10 (d, J = 8.0 Hz, 2H), 7.65 (d,J = 7.9 Hz, 2H), 7.29 (d, J = 4.9 Hz, 1H), 7.16 (d, J = 8.6 Hz, 2H),6.57 (d, J = 8.5 Hz, 2H), 3.07 (s, 3H), 2.26 (dd, J = 17.4, 7.0 Hz, 2H),2.16 (s, 3H), 1.53-1.33 (m, 2H), 1.27-1.13 (m, 2H), 0.75 (t, J = 7.2 Hz,3H) (2 exchangeable protons were not observed) 1.20 A 556.2 A 104

6-butyl-5-((3- fluorophenyl)(methyl)a- mino)-3-((4-(3- methylpyridin-4-yl)phenyl)sulfonyl) pyridine-2,4-diol ¹H NMR (500 MHz, DMSO-d₆) δ 8.58-8.44 (m, 2H), 8.09 (d, J = 8.0 Hz, 2H), 7.63 (d, J = 8.0 Hz, 2H), 7.29(d, J = 4.6 Hz, 1H), 7.17-7.08 (m, 1H), 6.49- 6.41 (m, 1H), 6.36 (d, J =7.4 Hz, 2H), 3.13-2.98 (m, 3H), 2.25 (s, 5H), 1.42 (br. s., 2H),1.24-1.14 (m, 2H), 0.75 (t, J = 7.3 Hz, 3H) (2 exchangeable protons werenot observed) 0.95 A 522.2 A 105

6-butyl-5-((3- chlorophenyl)(methyl)a- mino)-3-((4-(6-fluoro-2-methylpyridin-3- yl)phenyl)sulfonyl)pyri- dine-2,4-diol ¹H NMR (500 MHz,DMSO-d₆) δ 8.08 (d, J = 8.1 Hz, 2H), 7.88 (t, J = 8.2 Hz, 1H), 7.64 (d,J = 8.1 Hz, 2H), 7.19-7.09 (m, 2H), 6.70 (d, J = 7.6 Hz, 1H), 6.58 (br.s., 1H), 6.51 (d, J = 8.2 Hz, 1H), 3.08 (s, 3H), 2.38 (s, 3H), 2.33-2.21(m, 2H), 1.42 (dt, J = 15.0, 7.6 Hz, 2H), 1.24- 1.12 (m, 2H), 0.75 (t, J= 7.2 Hz, 3H) (2 exchangeable protons were not observed) 1.14 A 556.1 B106

6-butyl-3-((4-(2-fluoro- 3-methylpyridin-4- yl)phenyl)sulfonyl)-5-((3-fluorophenyl)(methyl)a- mino)pyridine-2,4-diol ¹H NMR (500 MHz, DMSO-d₆)δ 8.16- 8.09 (m, 3H), 7.67 (d, J = 8.0 Hz, 2H), 7.29 (d, J = 4.9 Hz,1H), 7.15 (d, J = 7.8 Hz, 1H), 6.49-6.43 (m, 1H), 6.37 (d, J = 9.2 Hz,2H), 3.08 (s, 3H), 2.27 (dd, J = 16.7, 6.6 Hz, 2H), 2.16 (s, 3H), 1.54-1.34 (m, 2H), 1.24-1.07 (m, 2H), 0.75 (t, J = 7.2 Hz, 3H) (2exchangeable protons were not observed) 1.12 A 540.2 A 107

6-butyl-5-((3- chlorophenyl)(methyl)a- mino)-3-((4-(2-fluoro-3-methylpyridin-4- yl)phenyl)sulfonyl)pyri- dine-2,4-diol ¹H NMR (500 MHz,DMSO-d₆) δ 8.18- 8.08 (m, 3H), 7.66 (d, J = 8.0 Hz, 2H), 7.29 (d, J =4.9 Hz, 1H), 7.15 (t, J = 8.1 Hz, 1H), 6.69 (d, J = 7.6 Hz, 1H), 6.58(br. s., 1H), 6.51 (d, J = 7.6 Hz, 1H), 3.08 (s, 3H), 2.27 (d, J = 19.2,6.4 Hz, 2H), 2.16 (s, 3H), 1.54-1.32 (m, 2H), 1.26- 1.13 (m, 2H), 0.76(t, J = 7.3 Hz, 3H) (2 exchangeable protons were not observed) 1.19 A556.2 A 108

6-butyl-5-((4- chlorophenyl)(methyl)a- mino)-3-((4-(3- methylpyridin-4-yl)phenyl)sulfonyl)pyri- dine-2,4-diol ¹H NMR (500 MHz, DMSO-d₆) δ 8.58-8.42 (m, 2H), 8.08 (d, J = 7.7 Hz, 2H), 7.63 (d, J = 7.6 Hz, 2H), 7.28(br. s., 1H), 7.15 (d, J = 8.2 Hz, 2H), 6.56 (d, J = 8.4 Hz, 2H),3.27-2.93 (m, 3H), 2.24 (br. s., 5H), 1.41 (br. s., 2H), 1.25-1.10 (m,2H), 074 (t, J = 7.2 Hz, 3H) (2 exchangeable protons were not observed)1.01 A 538.2 A 109

6-butyl-3-((4-(6-fluoro- 2-methylpyridin-3- yl)phenyl)sulfonyl)-5-((3-fluorophenyl)(methyl)a- mino)pyridine-2,4-diol ¹H NMR (500 MHz, DMSO-d₆)δ 8.09 (d, J = 8.2 Hz, 2H), 7.88 (s, 1H), 7.64 (d, J = 7.9 Hz, 2H), 7.14(dd, J = 15.6, 7.9 Hz, 2H), 6.46 (br. s., 1H), 6.38 (d, J = 9.2 Hz, 2H),3.09 (s, 3H), 2.39 (s, 3H), 2.29 (dd, J = 16.8, 9.5 Hz, 2H), 1.52-1.37(m, 2H), 1.27-1.14 (m, 2H), 0.76 (t, J = 7.2 Hz, 3H) (2 exchangeableprotons were not observed) 1.11 A 540.2 B 110

6-butyl-5-((3- chlorophenyl)(methyl)a- mino)-3-((4-(3- methylpyridin-4-yl)phenyl)sulfonyl)pyri- dine-2,4-diol ¹H NMR (500 MHz, DMSO-d₆) δ 8.77-8.61 (m, 2H), 8.17 (d, J = 8.2 Hz, 2H), 7.74 (d, J = 8.2 Hz, 2H), 7.58(d, J = 4.6 Hz, 1H), 7.22-7.11 (m, 1H), 6.73 (d, J = 7.7 Hz, 1H), 6.63(br. s., 1H), 6.54 (d, J = 7.8 Hz, 1H), 3.12 (s, 3H), 2.32 (s, 5H),1.57-1.33 (m, 2H), 1.26-1.14 (m, 2H), 0.75 (t, J= 7.2 Hz, 3H) (2exchangeable protons were not observed) 1.01 A 538.2 A 111

6-butyl-5-((4- chlorophenyl)(methyl)a- mino)-3-((4-(2- methylpyridin-3-yl)phenyl)sulfonyl)pyri- dine-2,4-diol ¹H NMR (500 MHz, DMSO-d₆) δ 8.69(d, J = 4.3 Hz, 1H), 8.15 (d, J = 8.1 Hz, 2H), 8.07 (d, J = 7.7 Hz, 1H),7.73 (d, J = 8.1 Hz, 2H), 7.68 (d, J = 6.4 Hz, 1H), 7.20 (d, J = 8.7 Hz,2H), 6.62 (d, J = 8.7 Hz, 2H), 3.11 (s, 3H), 2.51-2.48 (m, 3H),2.44-2.23 (m, 2H), 1.42 (dd, J = 15.6, 8.7 Hz, 2H), 1.27-1.13 (m, 2H),0.75 (t, J = 7.3 Hz, 3H) (2 exchangeable protons were not observed) 0.99A 538.2 A 112

6-butyl-5-((2- fluorophenyl)(methyl)a- mino)-3-((4-(3- methylpyridin-4-yl)phenyl)sulfonyl)pyri- dine-2,4-diol ¹H NMR (500 MHz, DMSO-d₆) δ 8.61-8.42 (m, 2H), 7.99 (d, H = 7.9 Hz, 2H), 7.51 (d, J = 7.9 Hz, 2H), 7.25(d, J = 4.9 Hz, 1H), 6.89 (d, J = 7.6 Hz, 2H), 6.63 (d, J = 7.6 Hz, 2H),3.05 (br. s., 3H), 2.30- 2.19 (m, 5H), 1.48-1.22 (m, 2H), 1.19- 1.10 (m,2H), 0.74 (t, J = 7.2 Hz, 3H) (2 exchangeable protons were not observed)0.96 A 522.3 A 113

3-((2-butyl-4,6- dihydroxy-5-((4-(3- methylpyridin-4- y)phenyl)sulfonyl)pyridine-3- yl)(methyl)amino)benzonitrile ¹H NMR (500 MHz, DMSO-d₆) δ8.52 (s, 1H), 8.46 (d, J = 4.6 Hz, 1H), 7.97 (d, J = 7.9 Hz, 2H), 7.50(d, J = 7.9 Hz, 2H), 7.25 (d, J = 4.6 Hz, 2H), 6.95 (d, J = 7.3 Hz, 1H),6.77 (br. s., 2H), 3.01 (s, 3H), 2.24 (s, 3H), 2.21-2.07 (m, 2H), 1.40(d, J = 7.9 Hz, 2H), 1.23-1.14 (m, 2H), 0.76 (t, J = 7.2 Hz, 3H) (2exchangeable protons were not observed) 0.81 A 529.0 A 114

5-(ethyl(phenyl)amino)- 3-((4-(6-fluoro-2- methylpyridin-3-yl)phenyl)sulfonyl)-6- (m-tolyl)pyridine-2,4-diol ¹H NMR (500 MHz,DMSO-d₆) δ 8.13 (d, J = 8.2 Hz, 2H), 7.89 (t, J = 8.1 Hz, 1H), 7.68 (d,J = 8.2 Hz, 2H), 7.26-7.07 (m, 7H), 6.68 (t, J = 7.2 Hz, 1H), 6.61 (d, J= 7.9 Hz, 2H), 3.30-3.02 (m, 2H), 2.40 (s, 3H), 2.19 (s, 3H), 0.83 (t, J= 7.2 Hz, 3H) (2 exchangeable protons were not observed) 1.10 A 570.3 A115

6-butyl-5-(3,4- dihydrobenzo[b][1,4]ox- azepin-5(2H)-yl)-3-((4-(6-fluoro-2- methylpyridin-3- yl)phenyl)sulfonyl)pyri- dine-2,4-diol ¹HNMR (500 MHz, DMSO-d₆) δ 8.11 (d, J = 8.0 Hz, 2H), 7.89 (t, J = 8.2 Hz,1H), 7.65 (d, J = 7.9 Hz, 2H), 7.13 (d, J = 6.1 Hz, 1H), 6.83 (d, J =7.7 Hz, 1H), 6.80-6.75 (m, 1H), 6.70-6.65 (m, 1H), 6.37 (d, J = 7.9 Hz,1H), 4.37-4.04 (m, 2H), 3.94-3.34 (m, 2H), 2.46-2.28 (m, 5H), 1.99 (br.s., 2H), 1.44-1.24 (m, 2H), 1.20-1.12 (m, 2H), 0.72 (t, J = 7.2 Hz, 3H)(2 exchangeable protons were not observed) 1.02 A 564.2 B 116

6-butyl-3-((4-(3- methylpyridin-4- yl)phenyl)sulfonyl)-5-(2-phenylpiperidin-1- yl)pyridine-2,4-diol ¹H NMR (500 MHz, DMSO-d₆) δ8.65- 8.45 (m, 2H), 7.88 (d, J = 8.0 Hz, 2H), 7.67 (d, J = 8.0 Hz, 2H),7.36-7.17 (m, 5H), 7.15-6.99 (m, 1H), 4.33 (d, J = 10.8 Hz, 1H),3.09-2.90 (m, 2H), 2.26 (s, 3H), 2.15-1.86 (m, 2H), 1.80- 1.61 (m, 4H),1.47-1.39 (m, 2H), 1.36- 1.29 (m, 2H), 1.16 (t, J = 7.2 Hz, 2H), 0.93(t, J = 7.1 Hz, 3H) (2 exchangeable protons were not observed) 0.97 A558.3 B 117

3-((2-butyl-5-((4-(6- fluoro-2-methylpyridin- 3-yl)phenyl)sulfonyl)-4,6-dihydroxypyridin-3- yl)(methyl)amino)benzonitrile ¹H NMR (500 MHz,DMSO-d₆) δ 7.92 (d, J = 8.1 Hz, 2H), 7.82 (t, J = 8.2 Hz, 1H), 7.45 (d,J = 8.0 Hz, 2H), 7.22 (t, J = 8.0 Hz, 1H), 7.09 (d, J = 8.2 Hz, 1H),6.92 (d, J = 7.3 Hz, 1H), 6.76-6.70 (m, 2H), 2.98 (s, 3H), 2.36 (s, 3H),2.21- 2.03 (m, 2H), 1.38 (d, J = 7.2 Hz, 2H), 1.22-1.13 (m, 2H), 0.75(t, J = 7.3 Hz, 3H) (2 exchangeable protons were not observed) 1.03 A547.0 A 118

6-butyl-3-((4-(6-fluoro- 2-methylpyridin-3- yl)phenyl)sulfonyl)-5-((2-fluorophenyl)(methyl)a- mino)pyridine-2,4-diol ¹H NMR (500 MHz, DMSO-d₆)δ 8.08 (d, J = 7.9 Hz, 2H), 7.89 (t, J = 8.1 Hz, 1H), 7.66 (d, J = 7.9Hz, 2H), 7.15-7.10 (m, 1H), 7.07-6.98 (m, 2H), 6.91 (t, J = 8.9 Hz, 1H),6.78 (d, J = 4.0 Hz, 1H), 3.13 (s, 3H), 2.39 (s, 3H), 2.37-2.32 (m, 2H),1.49-1.20 (m, 2H), 1.19-1.06 (m, 2H), 0.72 (t, J = 7.2 Hz, 3H) (2exchangeable protons were not observed) 1.07 A 540.3 A 119

3-((2-butyl-4,6- dihydroxy-5-((4-(2- methylpyridin-3-yl)phenyl)sulfonyl)pyri- din-3- yl)(methyl)amino)benzonitrile ¹H NMR(500 MHz, DMSO-d₆) δ 8.49 (d, J = 4.0 Hz, 1H), 7.98 (d, J = 7.9 Hz, 2H),7.63 (d, J = 7.3 Hz, 1H), 7.51 (d, J = 7.9 Hz, 2H), 7.35-7.31 (m, 1H),7.26 (t, J = 7.8 Hz, 1H), 6.97 (d, J = 7.3 Hz, 1H), 6.80 (d, J = 14.3Hz, 2H), 3.03 (s, 3H), 2.42 (s, 3H), 2.27-2.09 (m, 2H), 1.41 (d, J=5.5Hz, 2H), 1.25-1.14 (m, 2H), 0.76 (t, J = 7.2 Hz, 3H) (2 exchangeableprotons were not observed) 0.80 A 529.0 A 120

5-(ethyl(phenyl)amino)- 3-((4-(3-methylpyridin- 4-yl)phenyl)sulfonyl)-6-(m-tolyl)pyridine-2,4-diol ¹H NMR (500 MHz, DMSO-d₆) δ 8.61- 8.46 (m,2H), 8.14 (d, J = 8.2 Hz, 2H), 7.69 (d, J = 7.9 Hz, 2H), 7.30 (d, J =4.9 Hz, 1H) ,7.19 (dd, J = 18.8, 10.5 Hz, 5H), 7.09 (d, J = 7.3 Hz, 1H),6.68 (t, J = 6.9 Hz, 1H), 6.61 (d, J = 7.9 Hz, 2H), 3.28-3.02 (m, 2H),2.27 (s, 3H), 2.19 (s, 3H), 0.83 (t, J = 7.0 Hz, 3H) (2 exchangeableprotons were not observed) 0.84 A 552.3 A 122

5-(ethyl(phenyl)amino)- 3-((4-(2-fluoro-3- methylpyridin-4-yl)phenyl)sulfonyl)-6- (m-tolyl)pyridine-2,4-diol ¹H NMR (500 MHz,DMSO-d₆) δ 8.16 (d, J = 6.1 Hz, 3H), 7.70 (d, J = 7.9 Hz, 2H), 7.31 (d,J = 4.6 Hz, 1H), 7.25-7.15 (m, 5H), 7.10 (d, J = 7.3 Hz, 1H), 6.67 (t, J= 7.0 Hz, 1H), 6.62 (d, J = 7.9 Hz, 2H), 3.30-3.05 (m, 2H), 2.19 (d, J =6.7 Hz, 6H), 0.83 (t, J = 7.0 Hz, 3H) (2 exchangeable protons were notobserved) 1.10 A 570.3 A 123

6-butyl-5-(3,4- dihydrobenzo[b][1,4]ox- azepin-5(2H)-yl)-3-((4-(2-methylpyridin-3- yl)phenyl)sulfonyl)pyri- dine-2,4-diol ¹H NMR (500MHz, DMSO-d₆) δ 8.51 (d, J = 4.6 Hz, 1H), 8.10 (d, J = 7.9 Hz, 2H),7.73-7.58 (m, 3H), 7.39-7.28 (m, 1H), 6.83 (d, J = 7.6 Hz, 1H), 6.77 (s,1H), 6.69-6.63 (m, 1H), 6.36 (d, J = 7.9 Hz, 1H), 4.37-4.04 (m, 2H),3.73- 3.43 (m, 2H), 2.44 (s, 3H), 2.37-2.26 (m, 2H), 2.05-1.91 (m, 2H),1.42-1.23 (m, 2H), 1.20-1.13 (m, 2H), 0.73 (t, J = 7.2 Hz, 3H) (2exchangeable protons were not observed) 0.88 A 546.3 B 124

6-butyl-5-((2- fluorophenyl)(methyl)a- mino)-3-((4-(2- methylpyridin-3-yl)phenyl)sulfonyl)pyri- dine-2,4-diol ¹H NMR (500 MHz, DMSO-d₆) δ 8.50(d, J = 3.7 Hz, 1H), 8.01 (d, J = 8.2 Hz, 2H), 7.65 (d, J = 7.3 Hz, 1H),7.56 (d, J = 7.9 Hz, 2H), 7.38-7.30 (m, 1H), 7.01- 6.91 (m, 2H),6.78-6.65 (m, 2H), 3.08 (s, 3H), 2.44 (s, 3H), 2.27 (br. s., 2H),1.47-1.23 (m, 2H), 1.20-1.11 (m, 2H), 0.74 (t, J = 7.2 Hz, 3H) (2exchangeable protons were not observed) 0.88 A 522.3 A 125

6-butyl-3-((4-(2-fluoro- 3-methylpyridin-4- yl)phenyl)sulfonyl)-5-((2-fluorophenyl)(methyl)a- mino)pyridine-2,4-diol ¹H NMR (500 MHz, DMSO-d₆)δ 8.14 (d, J = 4.9 Hz, 1H), 8.09 (d, J = 7.9 Hz, 2H), 7.65 (d, J = 7.9Hz, 2H), 7.29 (d, J = 4.9 Hz, 1H), 7.05-6.97 (m, 2H), 6.85 (br. s., 1H),6.75 (br. s., 1H), 3.11 (s, 3H), 2.31 (br. s., 2H), 2.16 (s, 3H), 1.23(br. s., 2H), 1.15 (d, J = 5.2 Hz, 2H), 0.72 (t, J = 7.2 Hz, 3H) (2exchangeable protons were not observed) 1.11 A 540.3 A 126

6-butyl-3-((4-(6-fluoro- 2-methylpyridin-3- yl)phenyl)sulfonyl)-5-(2-phenylpiperidin-1- yl)pyridine-2,4-diol ¹H NMR (500 MHz, DMSO-d₆) δ7.92- 7.83 (m, 3H), 7.66 (d, J = 7.9 Hz, 2H), 7.27-7.24 (m, 2H), 7.21(t, J = 7.3 Hz, 2H), 7.16-7.09 (m, 2H), 4.33 (d, J = 10.7 Hz, 1H),3.51-3.16 (m, 2H), 3.08-2.84 (m, 2H), 2.39 (s, 3H), 1.92- 1.59 (m, 5H),1.51-1.30 (m, 5H), 0.93 (t, J = 7.0 Hz, 3H) (2 exchangeable protons werenot observed) 1.18 A 576.3 B 127

6-butyl-5-(3,4- dihydrobenzo[b][1,4]ox- azepin-5(2H)-yl)-3-((4-(2-fluoro-3- methylpyridin-4- yl)phenyl)sulfonyl)pyri- dine-2,4-diol ¹HNMR (500 MHz, DMSO-d₆) δ 8.14 (d, J = 4.9 Hz, 1H), 8.08 (d, J = 7.9 Hz,2H), 7.60 (d, J = 7.6 Hz, 2H), 7.28 (d, J = 4.9 Hz, 1H), 6.78 (d, J =7.6 Hz, 1H), 6.74-6.67 (m, 1H), 6.61 (d, J = 7.0 Hz, 1H), 6.31 (d, J =7.9 Hz, 1H), 4.36-4.03 (m, 2H), 3.68 (d, J = 10.1 Hz, 1H), 2.89 (d, J =7.3 Hz, 1H), 2.40-2.24 (m, 2H), 2.17 (s, 3H), 2.05-1.88 (m, 2H), 1.44-1.25 (m, 2H), 1.21-1.12 (m, 2H), 0.74 (t, J = 7.2 Hz, 3H) (2exchangeable protons were not observed) 1.08 A 564.3 A 128

6-butyl-3-((4-(2-fluoro- 3-methylpyridin-4- yl)phenyl)sulfonyl)-5-(2-phenylpiperidin-1- yl)pyridine-2,4-diol ¹H NMR (500 MHz, DMSO-d₆) δ8.15 (d, J = 4.6 Hz, 1H), 7.90 (d, J = 7.9 Hz, 2H), 7.66 (d, J = 7.9 Hz,2H), 7.30-7.15 (m, 5H), 7.11 (d, J = 6.7 Hz, 1H), 4.34 (d, J = 10.7 Hz,1H), 3.54 (br. s., 2H), 3.06-2.78 (m, 2H), 2.16 (s, 3H), 1.90- 1.58 (m,5H), 1.50-1.28 (m, 5H), 0.92 (t, J = 6.9 Hz, 3H) (2 exchangeable protonswere not observed) 1.18 A 576.3 B 129

6-butyl-5-(3,4- dihydrobenzo[b][1,4]ox- azepin-5(2H)-yl)-3-((4-(3-methylpyridin-4- yl)phenyl)sulfonyl)pyri- dine-2,4-diol ¹H NMR (500MHz, DMSO-d₆) δ 8.65- 8.39 (m, 2H), 8.00 (d, J = 7.6 Hz, 2H), 7.50 (d, J= 7.6 Hz, 2H), 7.26 (br. s., 1H), 6.77-6.69 (m, 1H), 6.65-6.60 (m, 1H),6.53 (s, 1H), 6.24 (d, J = 7.9 Hz, 1H), 4.37-4.05 (m, 2H), 3.72-3.20 (m,2H), 2.25 (s, 5H), 1.91 (s, 2H), 1.32 (d, J = 7.0 Hz, 2H), 1.22-1.10 (m,2H), 0.73 (t, J = 7.2 Hz, 3H) (2 exchangeable protons were not observed)0.85 A 546.3 A 130

(3-(3,5-difluoropyridin- 2-yl)pyrrolidin-1-yl)(5- (ethyl(phenyl)amino)-2,4-dihydroxy-6-(m- tolyl)pyridin-3- yl)methanone ¹H NMR (500 MHz,DMSO-d₆) δ 8.48 (br. s., 1H), 7.94 (d, J = 11.0 Hz, 1H), 7.24-7.01 (m,7H), 6.67 (br. s., 1H), 6.56 (d, J = 7.5 Hz, 1H), 3.94-3.37 (m, 4H),3.27-2.90 (m, 2H), 2.18 (br. s., 6H), 0.79 (br. s., 3H) (2 exchangeableprotons were not observed) 0.95 A 531.3 A 131

3-((4-bromophenyl)sulfonyl)- 5-(ethyl(phenyl)amino)-6-(m-tolyl)pyridine-2,4-diol ¹H NMR (400 MHz, CHLOROFORM- d) δ11.76-11.43 (m, 1H), 10.56- 10.17 (m, 1H), 7.75 (d, J = 8.4 Hz, 2H),7.49 (d, J = 8.4 Hz, 2H), 7.35-7.30 (m, 4H), 7.25 (s, 2H), 6.92-6.82 (m,1H), 6.68 (d, J = 7.9 Hz, 2H), 3.44-3.12 (m, 2H), 2.37 (s, 3H), 0.94 (t,J = 7.2 Hz, 3H) 1.26 A 539.2 B 132

(3-(3,5-difluoropyridin- 2-yl)pyrrolidin-1-yl)(5- (ethyl(phenyl)amino)-2,4-dihydroxy-6-(m- tolyl)pyridin-3- yl)methanone ¹H NMR (500 MHz,DMSO-d₆) δ 8.62- 8.42 (m, 1H), 8.06-7.85 (m, 1H), 7.27- 6.99 (m, 6H),6.75-6.44 (m, 3H), 3.38 (br. s., 1H), 3.18 (d, J = 4.3 Hz, 3H), 3.02-2.84 (m, 1H), 2.19 (br. s., 4H), 1.92 (s, 1H), 1.29-1.11 (m, 2H), 0.78(br. s., 3H) (2 exchangeable protons were not observed) 1.03 A 531.3 A133

6-butyl-5-((3,5- dimethylphenyl)(ethyl)a- mino)-3-((4-(3-methylpyridin-4- yl)phenyl)sulfonyl)pyri- dine-2,4-diol ¹H NMR (500 MHz,DMSO-d₆) δ 8.58- 8.46 (m, 2H), 8.08 (d, J = 8.2 Hz, 2H), 7.65 (d, J =7.9 Hz, 2H), 7.28 (br. s., 1H), 6.31 (br. s., 1H), 6.16 (s, 2H), 2.50-2.48 (m, 2H), 2.25 (s, 5H), 2.15 (s, 6H), 1.48-1.36 (m, 2H), 1.20-1.14(m, 2H), 1.11 (t, J = 6.9 Hz, 3H), 0.73 (t, J = 7.2 Hz, 3H) (2exchangeable protons were not observed) 0.99 A 546.3 A 134

3-((4- bromophenyl)sulfonyl)- 6-butyl-5-((3,5- dimethylphenyl)(ethyl)a-mino)pyridine-2,4-diol ¹H NMR (400 MHz, CHLOROFORM- d) δ 11.55 (br. s.,1H), 10.74 (br. s., 1H), 7.94 (d, J = 8.8 Hz, 2H), 7.67 (d, J = 8.6 Hz,2H), 6.49 (s, 1H), 6.22 (s, 2H), 3.70-3.45 (m, 2H), 2.55 (t, J = 8.0 Hz,2H), 2.28 (s, 6H), 1.68-1.58 (m, 2H), 1.41-1.31 (m, 2H), 1.25 (t, J =7.2 Hz, 3H), 0.91 (t, J = 7.3 Hz, 3H) 1.21 A 533.2 B 135

6-butyl-5-((3,5- dimethylphenyl)ethyl)a- mino)-3-((4-(6-fluoro-2-methylpyridin-3- yl)phenyl)sulfonyl)pyri- dine-2,4-diol ¹H NMR (500 MHz,DMSO-d₆) δ 8.02 (d, J = 7.7 Hz, 2H), 7.90-7.78 (m, 1H), 7.58 (d, J = 7.1Hz, 2H), 7.10 (d, J = 7.8 Hz, 1H), 6.26 (br. s., 1H), 6.12 (br. s., 2H),3.16 (br. s., 2H), 2.37 (s, 3H), 2.31- 2.19 (m, 2H), 2.13 (s, 6H), 1.40(br. s., 2H), 1.19-1.12 (m, 2H), 1.07 (t, J = 6.9 Hz, 3H), 0.72 (t, J =7.0 Hz, 3H) (2 exchangeable protons were not observed) 1.18 A 564.3 A136

6-butyl-5-((3,5- dimethylphenyl)(ethyl)a- mino)-3-((4-(2-fluoro-3-methylpyridin-4- yl)phenyl)sulfonyl)pyri- dine-2,4-diol ¹H NMR (500 MHz,DMSO-d₆) δ 8.12 (d, J = 4.5 Hz, 1H), 8.07 (d, J = 7.7 Hz, 2H), 7.63 (d,J = 7.3 Hz, 2H), 7.27 (d, J = 4.3 Hz, 1H), 6.28 (br. s., 1H), 6.13 (br.s., 2H), 3.57-3.19 (m, 2H), 2.40- 2.20 (m, 2H), 2.17-2.09 (m, 9H), 1.39(d, J = 7.6 Hz, 2H), 1.19-1.12 (m, 2H), 1.08 (t, J = 6.9 Hz, 3H), 0.72(t, J = 7.2 Hz, 3H) (2 exchangeable protons were not observed) 1.16 A564.3 A 137

4′-((6-butyl-5-((3- cyanophenyl)(methyl)a- mino)-2,4-dihydroxypyridin-3- yl)sulfonyl)-N-methyl- [1,1′-biphenyl]-2-carboxamide ¹H NMR (500 MHz, DMSO-d₆) δ 8.15 (d, J = 4.6 Hz, 1H), 7.95(d, J = 7.9 Hz, 2H), 7.54-7.47 (m, 3H), 7.45-7.38 (m, 3H), 7.30 (t, J =7.9 Hz, 1H), 7.02 (d, J = 7.3 Hz, 1H), 6.89-6.80 (m, 2H), 3.05 (s, 3H),2.58 (d, J = 4.6 Hz, 3H), 2.32- 2.14 (m, 2H), 1.39 (dd, J = 16.3, 7.2Hz, 2H), 1.19-1.11 (m, 2H), 0.72 (t, J = 7.3 Hz, 3H) (2 exchangeableprotons were not observed) 1.14 A 571.2 A 138

4′-((6-butyl-5-((3- cyanophenyl)(methyl)a- mino)-2,4-dihydroxypyridin-3- yl)sulfonyl)-[1,1′- biphenyl]-2-carboxamide ¹H NMR(500 MHz, DMSO-d₆) δ 7.94 (br. s., 1H), 7.73 (br. s., 1H), 7.53-7.35 (m,5H), 7.30 (br. s., 1H), 7.24 (br. s., 1H), 6.93 (br., s., 1H), 6.74 (br.s., 2H), 3.47 (br. s., 2H), 2.98 (br. s., 2H), 1.92 (br. s., 2H), 1.23(s, 5H), 0.74 (br. s., 3H) (2 exchangeable protons were not observed)1.07 A 557.3 A 139

4′-((6-butyl-5-((3- cyanophenyl)(methyl)a- mino)-2,4-dihydroxypyridin-3- yl)sulfonyl)-N,N- dimethyl-[1,1′-biphenyl]-2-carboxamide ¹H NMR (500 MHz, DMSO-d₆) δ 7.96 (d, J = 7.0 Hz,2H), 7.61-7.46 (m, 5H), 7.36 (d, J = 7.2 Hz, 1H), 7.30-7.25 (m, 1H),7.01 (d, J = 7.2 Hz, 1H), 6.92-6.77 (m, 2H), 2.55 (s, 6H), 2.49 (br. s.,3H), 2.33-2.13 (m, 2H), 1.46-1.34 (m, 2H), 1.21-1.14 (m, 2H), 0.75 (t, J= 7.3 Hz, 3H) (2 exchangeable protons were not observed) 1.11 A 585.3 A140

4′-((6-butyl-5-((3,5- dimethylphenyl)(ethyl)a- mino)-2,4-dihydroxypyridin-3- yl)sulfonyl)-N,N- dimethyl-[1,1′-biphenyl]-2-carboxamide ¹H NMR (500 MHz, DMSO-d₆) δ 7.91 (d, J = 7.9 Hz,2H), 7.56-7.42 (m, 5H), 7.35 (d, J = 7.3 Hz, 1H), 6.19 (br. s., 1H),6.08 (s, 2H), 2.75 (s, 2H), 2.55 (s, 6H), 2.11 (s, 8H), 1.41 (br. s.,2H), 1.20- 1.12 (m, 2H), 1.04 (t, J = 7.0 Hz, 3H), 0.74 (t, J = 7.3 Hz,3H) (2 exchangeable protons were not observed) 1.25 A 602.3 A 141

4′-((5- (ethyl(phenyl)amino)- 2,4-dihydroxy-6-(m- tolyl)pyridin-3-yl)sulfonyl)-N,N- dimethyl-[1,1′- biphenyl]-2-carboxamide ¹H NMR (500MHz, DMSO-d₆) δ 7.93 (d, J = 8.0 Hz, 2H), 7.56-7.33 (m, 6H), 7.11 (br.s., 3H), 7.07-7.00 (m, 3H), 6.55-6.45 (m, 3H), 3.05 (d, J = 6.6 Hz, 2H),2.76 (s, 3H), 2.45 (br. s., 3H), 2.17 (s, 3H), 0.71 (t, J = 7.1 Hz, 3H)(2 exchangeable protons were not observed) 1.21 A 608.4 A 142

4′-((6-butyl-5-(3,4- dihydrobenzo[b][1,4]ox- azepin-5(2H)-yl)-2,4-dihydroxypyridin-3- yl)sulfonyl)-N,N- dimethyl-[1,1′-biphenyl]-2-carboxamide ¹H NMR (500 MHz, DMSO-d₆) δ 7.91 (d, J = 8.1 Hz,2H), 7.52 (d, J = 7.5 Hz, 1H), 7.47 (d, J = 3.3 Hz, 2H), 7.41 (d, J =8.1 Hz, 2H), 7.34 (d, J = 7.5 Hz, 1H), 6.71 (d, J = 7.6 Hz, 1H),6.65-6.59 (m, 1H), 6.52 (t, J = 7.4 Hz, 1H), 6.22 (d, J = 7.9 Hz, 1H),4.30-4.03 (m, 2H), 3.73- 3.56 (m, 2H), 2.31-2.14 (m, 2H), 1.98- 1.79 (m,8H), 1.37-1.25 (m, 2H), 1.18- 1.07 (m, 2H), 0.72 (t, J = 7.2 Hz, 3H) (2exchangeable protons were not observed) 1.14 A 602.2 B 143

4′-((6-butyl-5-((3,5- dimethylphenyl)(ethyl)a- mino)-2,4-dihydroxypyridin-3- yl)sulfonyl)-[1,1′- biphenyl]-2-carboxamide )⁺. ¹HNMR (500 MHz, DMSO-d₆) δ 7.89 (d, J = 7.6 Hz, 2H), 7.73 (br. s., 1H),7.47 (d, J = 11.3 Hz, 5H), 7.38 (d, J = 7.3 Hz, 1H), 7.30 (br. s., 1H),6.18 (br. s., 1H), 6.08 (br. s., 2H), 3.32-3.14 (m, 2H), 2.21-2.05 (m,8H), 1.41 (br. s., 2H), 1.16 (d, J = 7.3 Hz, 2H), 1.05 (t, J = 7.0 Hz,3H), 0.74 (t, J = 7.3 Hz, 3H) (2 exchangeable protons were not observed)1.15 A 574.3 A 144

4′-((5- (ethyl(phenyl)amino)- 2,4-dihydroxy-6-(m- tolyl)pyridin-3-yl)sulfonyl)-[1,1′- biphenyl]-2-carboxamide ¹H NMR (500 MHz, DMSO-d₆) δ8.02 (d, J = 7.9 Hz, 2H), 7.82 (br. s., 1H), 7.61- 7.44 (m, 4H), 7.42(d, J = 7.6 Hz, 1H), 7.35 (br. s., 1H), 7.20-7.12 (m, 4H), 7.08 (d, J =6.7 Hz, 1H), 6.63 (br. s., 1H), 6.57 (d, J = 7.3 Hz, 2H), 3.22-3.03 (m,2H), 2.18 (s, 3H), 1.29-1.20 (m, 2H), 0.79 (t, J = 6.9 Hz, 3H) (2exchangeable protons were not observed) 1.13 A 580.3 A 145

4′-((5- (ethyl(phenyl)amino)- 2,4-dihydroxy-6-(m- tolyl)pyridin-3-yl)sulfonyl)-N-methyl- [1,1′-biphenyl]-2-carboxamide ¹H NMR (500 MHz,DMSO-d₆) δ 8.12 (d, J = 4.0 Hz, 1H), 7.95-7.89 (m, 2H), 7.51 (d, J = 6.7Hz, 1H), 7.45-7.39 (m, 5H), 7.11 (br. s., 3H), 7.08-7.02 (m, 3H), 6.52(t, J = 6.9 Hz, 1H), 6.47 (d, J = 7.9 Hz, 2H), 3.07 (d, J = 6.7 Hz, 2H),2.59 (d, J = 4.0 Hz, 3H), 2.17 (s, 3H), 0.72 (t, J = 7.0 Hz, 3H) (2exchangeable protons were not observed) 1.18 A 594.3 A 146

4′-((6-butyl-5-(3,4- dihydrobenzo[b][1,4]ox- azepin-5(2H)-yl)-2,4-dihydroxypyridin-3- yl)sulfonyl)-N-methyl- [1,1′-biphenyl]-2-carboxamide¹H NMR (500 MHz, DMSO-d₆) δ 8.12 (br. s., 1H), 7.96-7.90 (m, 2H), 7.51(d, J = 5.2 Hz, 1H), 7.44 (d, J = 6.4 Hz, 5H), 6.73 (d, J = 7.3 Hz, 1H),6.69-6.62 (m, 1H), 6.54 (br. s., 1H), 6.27 (d, J = 7.9 Hz, 1H),4.32-4.07 (m, 2H), 3.70 (br. s., 2H), 2.59 (d, J = 4.3 Hz, 3H),2.33-2.16 (m, 2H), 1.92 (s, 2H), 1.41-1.27 (m, 2H), 1.21-1.13 (m, 2H),0.74 (t, J = 7.2 Hz, 3H) (2 exchangeable protons were not observed) 1.11A 588.2 A 147

4′-((6- (cyclopropylmethyl)-5- (ethyl(phenyl)amino)-2,4-dihydroxypyridin-3- yl)sulfonyl)-[1,1′- biphenyl]-2-carboxamide ¹HNMR (500 MHz, DMSO-d6) δ 7.82 (d, J = 7.6 Hz, 2H), 7.63 (br s., 1H),7.43- 7.25 (m, 6H), 7.20 (br. s., 1H), 6.95 (t, J = 7.5 Hz, 2H),6.48-6.42 (m, 1H), 6.39 (d, J = 7.9 Hz, 2H), 3.33-3.20 (m, J = 7.6 Hz,2H), 2.03 (dd, J = 18.5, 6.6 Hz, 2H), 0.96 (t, J = 7.0 Hz, 3H), 0.74 (d,J = 16.8 Hz, 1H), 0.27-0.13 (m, 2H), 0.04-−0.04 (m, 1H), −0.08-−0.16 (m,1H) (2 exchangeable protons not observed) 1.15 A 544.3 A 148

4′-((5- (ethyl(phenyl)amino)- 2,4-dihydroxy-6-(1- methyl-1H-pyrazol-3-yl)pyridin-3- yl)sulfonyl)-[1,1′- biphenyl]-2-carboxamide ¹H NMR (500MHz, DMSO-d6) δ 8.06 (d, J = 7.9 Hz, 2H), 7.95 (s, 1H), 7.85 (br. s.,1H), 7.74 (br. s., 1H), 7.64 (d, J = 7.7 Hz, 2H), 7.57-7.37 (m, 4H),7.17 (d, J = 7.3 Hz, 2H), 6.72-6.61 (m, 3H), 6.31 (br. s., 1H),3.47-3.39 (m, 2H), 2.89 (s, 3H), 1.03 (t, J = 6.7 Hz, 3H) (4exchangeable protons not observed) 1.10 A 570.3 A 149

5-(ethyl(phenyl)amino)- 3-((4-(2-fluoro-3- methylpyridin-4-yl)phenyl)sulfonyl)-6- (1-methyl-1H-pyrazol- 4-yl)pyridine-2,4-diol ¹HNMR (500 MHz, DMSO-d6) δ 8.13 (d, J = 4.9 Hz, 1H), 8.11-8.05 (m, 3H),7.70 (s, 1H), 7.62 (d, J = 7.6 Hz, 2H), 7.27 (d, J = 4.9 Hz, 1H), 7.13(t, J = 7.5 Hz, 2H), 6.68-6.57 (m, 3H), 3.78 (s, 3H), 3.44 (m, 2H), 2.15(s, 3H), 0.98 (t, J = 7.0 Hz, 3H) (2 exchangeable protons not observed)1.11 A 560.4 A 150

5-(ethyl(phenyl)amino)- 6-(1-methyl-1H- pyrazol-4-yl)-3-((4-(2-methylpyridin-3- yl)phenyl)sulfonyl)pyri- dine-2,4-diol ¹H NMR (500 MHz,DMSO-d6) δ 8.51 (d, J = 4.0 Hz, 1H), 8.14-8.05 (m, 3H), 7.74 (s, 1H),7.71-7.61 (m, 3H), 7.39- 7.32 (m, 1H), 7.18 (t, J = 7.6 Hz, 2H), 6.70(t, J = 7.2 Hz, 1H), 6.65 (d, J = 7.9 Hz, 2H), 3.78 (s, 3H), 3.56-3.40(m, 2H), 2.43 (s, 3H), 1.02 (t, J = 7.2 Hz, 3H) (2 exchangeable protonsnot observed) 0.83 A 542.3 A 151

4′-((5- (ethyl(phenyl)amino)- 2,4-dihydroxy-6-(1- methyl-1H-pyrazol-4-yl)pyridin-3- yl)sulfonyl)-N-methyl- [1,1′-biphenyl]-2-carboxamide ¹HNMR (500 MHz, DMSO-d6) δ 8.18 (br. s., 1H), 8.12 (s, 1H), 8.01 (d, J =7.6 Hz, 2H), 7.72 (s, 1H), 7.57-7.51 (m, 3H), 7.49-7.41 (m, 3H), 7.15(t, J = 7.3 Hz, 2H), 6.70-6.60 (m, 3H), 3.79 (s, 3H), 3.56-3.36 (m, 2H),2.59 (d, J = 4.3 Hz, 3H), 1.00 (t, J = 7.0 Hz, 3H) (2 exchangeableprotons not observed) 1.02 A 584.4 A 152

5-(ethyl(phenyl)amino)- 3-((4-(6-fluoro-2- methylpyridin-3-yl)phenyl)sulfonyl)-6- (1-methyl-1H-pyrazol- 4-yl)pyridine-2,4-diol ¹HNMR (500 MHz, DMSO-d6) δ 8.15 (br. s., 1H), 8.07 (d, J = 7.3 Hz, 2H),7.87 (t, J = 7.8 Hz, 1H), 7.71 (br. s., 1H), 7.60 (d, J = 6.1 Hz, 2H),7.19-7.07 (m, 3H), 6.68-6.59 (m, 3H), 3.80 (s, 3H), 3.52- 3.36 (m, 2H),2.38 (s, 3H), 0.99 (t, J = 6.6 Hz, 3H) (2 exchangeable protons notobserved) 1.13 A 560.3 A 153

N-cyclopropyl-4′-((5- (ethyl(phenyl)amino)- 2,4-dihydroxy-6-(1-methyl-1H-pyrazol-4- yl)pyridin-3- yl)sulfonyl)-[1,1′-biphenyl]-2-carboxamide ¹H NMR (500 MHz, DMSO-d6) δ 7.98 (br. s., 1H),7.92 (d, J = 3.7 Hz, 1H), 7.66 (d, J = 7.9 Hz, 2H), 7.35 (s, 1H), 7.24(t, J = 7.3 Hz, 1H), 7.20-7.09 (m, 5H), 6.81 (t, J = 7.6 Hz, 2H),6.32-6.25 (m, 3H), 3.54 (s, 3H), 3.27-3.05 (m, 4H), 0.67 (t, J = 7.2 Hz,3H), 0.26 (d, J = 5.8 Hz, 2H), 0.01 (br. s., 2H) (1 exchangeable protonnot observed) 1.84 A 610.0 A 154

4′-((5- (ethyl(phenyl)amino)- 2,4-dihydroxy-6-(1- methyl-1H-pyrazol-4-yl)pyridin-3- yl)sulfonyl)-N,N- dimethyl-[1,1′- biphenyl]-2-carboxamide¹H NMR (500 MHz, DMSO-d6) δ 8.17 (br. s., 1H), 7.98 (d, J = 6.7 Hz, 2H),7.67 (br. s., 1H), 7.56-7.44 (m, 5H), 7.35 (d, J = 7.3 Hz, 1H), 7.10(br. s., 2H), 6.58 (d, J = 7.9 Hz, 3H), 3.78 (s, 3H), 3.47-3.34 (m, 3H),2.74 (s, 3H), 2.45 (br. s., 3H), 0.95 (t, J = 6.7 Hz, 3H) (1exchangeable proton not observed) 1.86 A 598.1 A 155

4′-((5- (ethyl(phenyl)amino)- 2,4-dihydroxy-6-(1- methyl-1H-pyrazol-4-yl)pyridin-3- yl)sulfonyl)-4-fluoro- [1,1′-biphenyl]-2-carboxamide ¹HNMR (500 MHz, DMSO-d6) δ 8.09 (br. s., 1H), 7.94 (br. s., 2H), 7.86 (br.s., 1H), 7.66 (br. s., 1H), 7.50 (br. s., 2H), 7.44 (br. s., 2H),7.39-7.25 (m, 2H), 7.11 (br. s., 2H), 6.59 (br. s., 3H), 3.77 (s, 3H),3.55-3.41 (m, 2H), 1.02- 0.89 (m, 3 H) (2 exchangeable protons notobserved) 1.04 A 588.3 A 156

5-(ethyl(phenyl)amino)- 6-(1-methyl-1H- pyraozl-4-yl)-3-((4-(3-methylpyridin-4- yl)phenyl)sulfonyl)pyri- dine-2,4-diol ¹H NMR (500 MHz,DMSO-d6) δ 8.52 (s, 1H), 8.46 (d, J = 4.9 Hz, 1H), 8.03 (s, 1H), 7.98(d, J = 7.9 Hz, 2H), 7.61 (s, 1H), 7.47 (d, J = 8.2 Hz, 2H), 7.24 (d, J= 4.9 Hz, 1H), 7.04 (t, J = 7.6 Hz, 2H), 6.56-6.48 (m, 3H), 3.76 (s,3H), 3.40- 3.23 (m, 2H), 2.24 (s, 3H), 0.90 (t, J = 7.2 Hz, 3H) (2exchangeable protons not observed) 0.89 A 542.3 A 157

3-((4-(6-fluoro-2- methylpyridin-3- yl)phenyl)sulfonyl)-5-(isopropyl(phen- yl)amino)- 6-(1-methyl-1H-pyrazol-3-yl)pyridine-2,4-diol ¹H NMR (500 MHz, DMSO-d6) δ 8.13 (d, J =8.2 Hz, 2H), 7.90 (t, J = 7.9 Hz, 1H), 7.70 (d, J = 9.8 Hz, 2H),7.28-7.04 (m, 4H), 6.67 (d, J = 7.6 Hz, 3H), 6.25 (br. s., 1H), 3.87 (s,3H), 2.40 (s, 3H), 1.29-1.13 (m, 4H), 0.92 (d, J = 6.1 Hz, 3H) (2exchangeable protons not observed) 2.24 A 574.2 A 158

4′-((2,4-dihydroxy-5- (isopropyl(phen- yl)amino)- 6-(1-methyl-1H-pyrazol-3-yl)pyridin-3- yl)sulfonyl)-N-methyl-[1,1′-biphenyl]-2-carboxamide ¹H NMR (500 MHz, DMSO-d6) δ 8.21- 8.14 (m,1H), 8.01 (m, 2H), 7.68 (m, 1H), 7.54 (m, 3H), 7.46 (m, 3H), 7.14 (m,2H), 6.64 (m, 3H), 6.24 (m, 1H), 4.15 (m, 1H), 3.44 (m, 3H), 2.59 (m,3H), 1.18 (m, 3H), 0.93 (m, 3H) (2 exchangeable protons not observed)1.93 A 598.1 A 159

4′-((2,4-dihydroxy-5- (isopropyl(phen- yl)amino)- 6-(1-methyl-1H-pyrazol-3-yl)pyridin-3- yl)sulfonyl)-N,N- dimethyl-[1,1′-biphenyl]-2-carboxamide ¹H NMR (500 MHz, DMSO-d6) δ 7.99- 7.86 (m, 2H),7.61 (br. s., 1H), 7.56- 7.37 (m, 5H), 7.33 (m, 1H), 7.02 (m, 2H),6.59-6.46 (m, 3H), 6.18 (m, 1H), 3.82 (m, 3H), 3.56 (m, 3H), 2.71 (m,3H), 1.06 (m, 3H), 0.88 (m, 3H) (2 exchangeable protons not observed)2.08 A 612.3 A 160

5-(3,3-dimethylindolin- 1-yl)-3-((4-(2-fluoro-3- methylpyridin-4-yl)phenyl)sulfonyl)-6- (1-methyl-1H-pyrazol- 3-yl)pyridine-2,4-diol ¹HNMR (500 MHz, DMSO-d6) δ 8.25- 7.99 (m, 3H), 7.73 (m, 1H), 7.67-7.49 (m,2H), 7.27 (m, 1H), 7.02 (m, 1H), 6.83 (m, 1H), 6.54 (m, 1H), 6.48 (m,1H), 5.97 (m, 1H), 3.88 (m, 2H), 3.39 (m, 3H), 2.15 (m, 3H), 1.37 (m,3H), 1.24 (m, 3H) (2 exchangeable protons not observed) 1.28 A 586.4 B161

4′-((2,4-dihydroxy-5- (isopropyl(phenyl)amino)- 6-(1-methyl-1H-pyrazol-3-yl)pyridin-3- yl)sulfonyl)-4-fluoro- [1,1′-biphenyl]-2-carboxamide ¹H NMR (500 MHz, DMSO-d6) δ 8.03 (d, J = 7.3 Hz, 2H), 7.90(m, 1H), 7.69 (m, 1H), 7.59 (m, 2H), 7.48 (m, 2H), 7.41-7.31 (m, 2H),7.15 (m, 2H), 6.64 (m, 3H), 6.24 (br. s., 1H), 4.16 (m, 1H), 3.86 (s,3H), 1.18 (d, J = 4.3 Hz, 3H), 0.92 (d, J = 5.8 Hz, 3H) (2 exchangeableprotons not observed) 1.94 A 602.4 A 162

N-cyclopropyl-4′-((2,4- dihydroxy-5- (isopropyl(phen- yl)amino)-6-(1-methyl-1H- pyrazol-3-yl)pyridin-3- y)sulfonyl)-[1,1′-biphenyl]-2-carboxamide ¹H NMR (500 MHz, DMSO-d6) δ 8.00 (m, 1H), 7.81(m, 2H), 7.45 (m, 1H), 7.37-7.20 (m, 6H), 6.93 (m, 2H), 6.43 (m, 3H),6.04 (m, 1H), 3.94 (m, 1H), 3.60 (br. s., 3H), 2.29 (m, 1H), 0.97 (br.s., 3H), 0.74 (br. s., 3H), 0.31 (d, J = 5.8 Hz, 2H), 0.00 (br. s., 2H)(2 exchangeable protons not observed) 2.05 A 624.2 A 163

4′-((2,4-dihydroxy-5- (isopropyl(phen- yl)amino)- 6-(1-methyl-1H-pyrazol-3-yl)pyridin-3- yl)sulfonyl)-N-methyl-[1,1′-biphenyl]-3-carboxamide ¹H NMR (500 MHz, DMSO-d6) δ 8.60 (m, 1H),8.19-8.01 (m, 3H), 7.97-7.79 (m, 4H), 7.68-7.56 (m, 2H), 7.11 (m, 2H),6.61 (m ,2H), 6.21 (br. s., 1H), 4.12 (m, 1H), 3.58 (br. s., 3H), 2.81(d, J = 4.3 Hz, 3H), 1.14 (br. s., 3H), 0.90 (br. s., 3H) (3exchangeable protons not observed) 2.04 A 598.1 A 164

3-((4-(2-fluoro-3- methylpyridin-4- yl)phenyl)sulfonyl)-5-(isopropyl(phen- yl)amino)- 6-(1-methyl-1H-pyrazol-3-yl)pyridine-2,4-diol ¹H NMR (500 MHz, DMSO-d6) δ 8.11 (m, 1H),7.98 (m, 2H), 7.62 (m, 1H), 7.47 (m, 2H), 7.37-7.12 (m, 2H), 7.01 (m,2H), 6.50 (m, 2H), 6.17 (m, 1H), 4.01 (m, 1H), 3.83 (br. s., 3H), 2.12(br. s., 3H), 1.03 (br. s., 3H), 0.87 (br. s., 3H) (2 exchangeableprotons not observed) 1.27 A 574.4 A 165

5-(iso- propyl(phenyl)amino)- 6-(1-methyl-1H- pyrazol-3-yl)-3-((4-(2-methylpyridin-3- yl)phenyl)sulfonyl)pyri- dine-2,4-diol ¹H NMR (500 MHz,DMSO-d6) δ 8.47 (d, J = 3.7 Hz, 1H), 7.94 (d, J = 6.4 Hz, 1H), 7.65-7.57(m, 2H), 7.44 (d, J = 7.0 Hz, 2H), 7.35-7.27 (m, 1H), 7.06- 6.96 (m,2H), 6.57-6.43 (m, 3H), 6.16 (br. s., 1H), 4.07-3.97 (m, 1H), 3.35 (br.s., 3H), 2.41 (br. s., 3H), 1.06 (d, J = 4.9 Hz, 3H), 0.89 (d, J = 4.6Hz, 3H) (2 exchangeable protons not observed) 1.00 A 556.4 A 166

4′-((2,4-dihydroxy-5- (isopropyl(phen- yl)amino)- 6-(1-methyl-1H-pyrazol-3-yl)pyridin-3- yl)sulfonyl)-[1,1′- biphenyl]-2-carboxamide ¹HNMR (500 MHz, DMSO-d6) δ 8.09- 7.96 (m, 2H), 7.85-7.76 (m, 1H), 7.72-7.63 (m, 1H), 7.61-7.38 (m, 5H), 7.34 (br. s., 1H), 7.26 (br. s., 1H),7.19-7.03 (m, 3H), 6.70-6.55 (m, 2H), 6.25-6.15 (m, 1H), 4.20-4.09 (m,1H), 3.35 (br. s., 3H), 1.28 (br. s., 3H), 0.98-0.82 (m, 3H) (2exchangeable protons not observed) 1.24 A 585.4 A 167- I

6-butyl-3-((4-(2-fluoro- 3-methylpyridin-4- yl)phenyl)sulfonyl)-5-(2-methyl-3,4- dihydroquinolin-1(2H)- yl)pyridine-2,4-diol ¹H NMR (500MHz, CHLOROFORM- d) δ 8.20 (d, J = 8.0 Hz, 2H), 8.12 (d, J = 4.7 Hz,1H), 7.50 (d, J = 7.7 H,z 2H), 7.12-7.03 (m, 2H), 7.01-6.94 (m, 1H),6.75-6.68 (m, 1H), 6.16 (d, J = 8.0 Hz, 1H), 3.84-3.56 (m, 1H),3.06-2.80 (m, 2H), 2.69-2.46 (m, 2H), 2.22 (s, 3H), 2.18-1.86 (m, 2H),1.48-1.32 (m, 4H), 1.26-1.08 (m, 3H), 0.95-0.84 (m, 3H) (2 exchangeableprotons not observed) 1.29 A 562.4 A 167- II

6-butyl-3-((4-(2-fluoro- 3-methylpyridin-4- yl)phenyl)sulfonyl)-5-(2-methyl-3,4- dihydroquinolin-1(2H)- yl)pyridine-2,4-diol ¹H NMR (500MHz, CHLOROFORM- d) δ 8.20 (d, J = 8.0 Hz, 2H), 8.12 (d, J = 4.7 Hz,1H), 7.50 (d, J = 7.7 Hz, 2H), 7.12-7.03 (m, 2H), 7.01-6.94 (m, 1H),6.75-6.68 (m, 1H), 6.16 (d, J = 8.0 Hz, 1H), 3.84-3.56 (m, 1H),3.06-2.80 (m, 2H), 2.69-2.46 (m, 2H), 2.22 (s, 3H), 2.18-1.86 (m, 2H),1.48-1.32 (m, 4H), 1.26-1.08 (m, 3H), 0.95-0.84 (m, 3H) (2 exchangeableprotons not observed) 1.29 A 562.4 A 168

4′-((6-butyl-5-(3,4- dihydrobenzo[b][1,4]ox- azepin-5(2H)-yl)-2,4-dihydroxypyridin-3- yl)sulfonyl)-[1,1′- biphenyl]-2-carboxamide ¹H NMR(500 MHz, DMSO-d6) δ 8.01 (d, J = 7.9 Hz, 2H), 7.79 (br. s., 1H), 7.57(d, J = 7.9 Hz, 2H), 7.54-7.49 (m, 1H), 7.49-7.44 (m, 2H), 7.42 (d, J =7.6 Hz, 1H), 7.34 (br. s., 1H), 6.80 (d, J = 7.6 Hz, 1H), 6.77-6.72 (m,1H), 6.67-6.60 (m, 1H), 6.35 (d, J = 7.9 Hz, 1H), 4.37-4.06 (m, 2H),3.68 (d, J = 9.8 Hz, 1H), 3.40- 3.15 (m, 1H), 2.45-2.24 (m, 2H), 1.91(s, 2H), 1.42-1.25 (m, 2H), 1.21-1.12 (m, 2H), 0.73 (t, J = 7.3 Hz, 3H)(2 exchangeable protons not observed) 1.18 A 574.2 A 169

6-butyl-3-((4-(3- methylpyridin-4- yl)phenyl)sulfonyl)-5-(2,3,4,5-tetrahydro-1H- benzo[b]azepin-1- yl)pyridine-2,4-diol ¹H NMR(500 MHz, DMSO-d6) δ 8.52 (s, 1H), 8.46 (d, J = 4.3 Hz, 1H), 8.01 (d, J= 7.9 Hz, 2H), 7.50 (d, J = 7.6 Hz, 2H), 7.26 (d, J = 4.3 Hz, 1H), 6.95(d, J = 7.0 Hz, 1H), 6.78 (t, J = 7.2 Hz, 1H), 6.64- 6.56 (m, 1H), 6.40(d, J = 7.9 Hz, 1H), 3.44-3.15 (m, 2H), 2.84-2.64 (m, 2H), 2.26 (s, 5H),2.15 (d, J = 8.9 Hz, 2H), 1.72-1.56 (m, 2H), 1.30 (br. s., 2H),1.17-1.06 (m, 2H), 0.70 (t, J = 7.0 Hz, 3H) (2 exchangeable protons notobserved) 1.06 A 544.3 B 170

3-((2-butyl-4,6- dihydroxy-5-((4-(3- methylpyridin-4-yl)phenyl)sulfonyl)pyri- din-3- yl)(ethyl)amino)benzonitrile ¹H NMR (500MHz, DMSO-d6) δ 8.67- 8.55 (m, 1H), 8.14 (d, J = 8.2 Hz, 2H), 7.71 (d, J= 8.2 Hz, 2H), 7.43 (br. s., 1H), 7.35 (t, J = 7.9 Hz, 1H), 7.28-7.13(m, 1H), 7.09 (d, J = 7.3 Hz, 1H), 7.05 (d, J = 5.8 Hz, 1H), 6.92 (d, J= 7.6 Hz, 1H), 3.49 (br. s., 2H), 2.29 (s, 5H), 1.41 (d, J = 17.1 Hz,2H), 1.20-1.10 (m, 5H), 0.71 (t, J = 7.3 Hz, 3H) (2 exchangeable protonsnot observed) 0.98 A 543.3 A 171

4′-((6-butyl-5-((2- fluorophenyl)(methyl)a- mino)-2,4-dihydroxypyridin-3- yl)sulfonyl)-N,N- dimethyl-[1,1′-biphenyl]-2-carboxamide ¹H NMR (500 MHz, DMSO-d6) δ 8.01 (d, J = 7.9 Hz,2H), 7.59-7.47 (m, 5H), 7.37 (d, J = 7.3 Hz, 1H), 7.07-6.95 (m, 2H),6.89 (br. s., 1H), 6.76 (br. s., 1H), 3.56-3.46 (m, 2H), 3.11 (s, 3H),2.92- 2.70 (m, 6H), 2.32 (br. s., 2H), 1.13 (d, J = 5.5 Hz, 2H), 0.70(t, J = 7.2 Hz, 3H) (2 exchangeable protons not observed) 1.18 A 578.3 A172

3-((2-butyl-5-((4-(2- fluoro-3-methylpyridin- 4-yl)phenyl)sulfonyl)-4,6-dihydroxypyridin-3- yl)(ethyl)amino)benzonitrile ¹H NMR (500 MHz,DMSO-d6) δ 8.10 (br. s., 1H), 8.01-7.90 (m, 2H), 7.48 (br. s., 2H), 7.22(br. s., 2H), 6.89 (d, J = 6.4 Hz, 1H), 6.79-6.64 (m, 2H), 3.50 (d, J =9.2 Hz, 2H), 2.27-2.05 (m, 5H), 1.37 (br. s., 2H), 1.15 (d, J = 7.0 Hz,2H), 1.02 (br. s., 3H), 0.71 (t, J = 7.0 Hz, 3H) (2 exchangeable protonsnot observed) 1.21 A 561.3 A 173

6-butyl-3-((4-(2- methylpyridin-3- yl)phenyl)sulfonyl)-5-(2,3,4,5-tetrahydro-1H- benzo[b]azepin-1- yl)pyridine-2,4-diol ¹H NMR(500 MHz, DMSO-d6) δ 8.50 (br. s., 1H), 8.11 (d, J = 7.9 Hz, 2H), 7.70-7.60 (m, 3H), 7.39-7.32 (m, 1H), 7.06 (d, J = 7.0 Hz, 1H), 6.93 (d, J =6.4 Hz, 1H), 6.73 (t, J = 7.0 Hz, 1H), 6.47 (d, J = 7.9 Hz, 1H), 3.49(br. s., 2H), 3.43- 3.22 (m, 2H), 2.92-2.73 (m, 2H), 2.44 (br. s., 3H),2.27 (d, J = 7.3 Hz, 2H), 1.94- 1.74 (m, 2H), 1.70-1.47 (m, 2H), 1.45-1.28 (m, 2H), 0.69 (t, J = 6.6 Hz, 3H) (2 exchangeable protons notobserved) 1.09 A 544.3 B 174

4′-((6-butyl-5-((2- fluorophenyl)(methyl)a- mino)-2,4-dihydroxypyridin-3- yl)sulfonyl)-[1,1′- biphenyl]-2-carboxamide ¹H NMR(500 MHz, DMSO-d6) δ 8.00 (d, J = 7.9 Hz, 2H), 7.83 (br. s., 1H), 7.60(d, J = 7.7 Hz, 2H), 7.55-7.36 (m, 5H), 7.09-6.98 (m, 2H), 6.89 (br. s.,1H), 6.76 (br. s, 1H), 3.12 (br. s., 3H), 2.44- 2.26 (m, 2H), 1.42 (br.s., 2H), 1.15 (br. s., 2H), 0.72 (t, J = 7.0 Hz, 3H) (2 exchangeableprotons not observed) 1.14 A 550.3 A 175

3-((2-butyl-4,6- dihydroxy-5-((4-(2- methylpyridin-3-yl)phenyl)sulfonyl)pyri- dine-3- yl)(ethyl)amino)benzonitrile ¹H NMR(500 MHz, DMSO-d6) δ 8.45 (br. s., 1H), 7.92 (d, J = 8.2 Hz, 2H), 7.60(d, J = 7.3 Hz, 1H), 7.43 (d, J = 7.9 Hz, 2H), 7.34-7.29 (m, 1H), 7.21(t, J = 7.8 Hz, 1H), 6.89 (d, J = 7.3 Hz, 1H), 6.75 (d, J = 8.5 Hz, 1H),6.66 (br. s., 1H), 3.44- 3.29 (m, 2H), 2.39 (s, 3H), 2.25-2.05 (m, 2H),1.36 (br. s., 2H), 1.18-1.10 (m, 2H), 1.02 (t, J = 7.0 Hz, 3H), 0.71 (t,J = 7.2 Hz, 3H) (2 exchangeable protons were not observed) 0.96 A 543.3A 176

4′-((6-butyl-5-((2- fluorophenyl)(methyl)a- mino)-2,4-dihydroxypyridin-3- yl)sulfonyl)-N-methyl- [1,1′-biphenyl]-2-carboxamide¹H NMR (500 MHz, DMSO-d6) δ 8.10 (d, J = 4.6 Hz, 1H), 7.98-7.83 (m, 2H),7.50 (d, J = 6.4 Hz, 1H), 7.42 (br. s., 5H), 7.00-6.83 (m, 2H), 6.62 (d,J = 7.0 Hz, 2H), 3.03 (br. s., 3H), 2.58 (d, J = 4.6 Hz, 3H), 2.25-2.17(m, 2H), 1.38 (br. s., 2H), 1.18-1.09 (m, 2H), 0.73 (t, J = 7.2 Hz, 3H)(2 exchangeable protons were not observed) 1.14 A 564.3 A 177

6-butyl-3-((4-(6-fluoro- 2-methylpyridin-3- yl)phenyl)sulfonyl)-5-(2,3,4,5-tetrahydro-1H- benzo[b]azepin-1- yl)pyridine-2,4-diol ¹H NMR(500 MHz, DMSO-d6) δ 8.14 (d, J = 7.7 Hz, 2H), 7.89 (d, J = 8.0 Hz, 1H),7.67 (d, J = 7.2 Hz, 2H), 7.17-7.06 (m, 2H), 6.98 (br. s., 1H), 6.77(br. s., 1H), 6.50 (d, J = 7.4 Hz, 1H), 3.46 (br. s., 2H), 2.76 (br. s.,2H), 2.39 (br. s., 3H), 2.29 (d, J = 7.3 Hz, 2H), 1.97-1.74 (m, 2H),1.72-1.48 (m, 2H), 1.47-1.30 (m, 2H), 1.13 (br. s., 2H), 0.69 (br. s.,3H) (2 exchangeable protons were not observed) 1.29 A 562.3 B 178

3-((2-butyl-5-((4-(6- fluoro-2-methylpyridin- 3-yl)phenyl)sulfonyl)-4,6-dihydroxypyridin-3- yl)(ethyl)amino)benzonitrile ¹H NMR (500 MHz,DMSO-d6) δ 8.06 (d, J = 8.0 Hz, 2H), 7.87 (t, J = 8.1 Hz, 1H), 7.61 (d,J = 7.7 Hz, 2H), 7.30 (t, J = 7.9 Hz, 1H), 7.12 (d, J = 8.0 Hz, 1H),7.03 (d, J = 7.4 Hz, 1H), 6.95 (br. s., 1H), 6.87 (d, J = 8.3 Hz, 1H),3.52-3.39 (m, 2H), 2.38 (s, 3H), 2.33-2.19 (m, 2H), 1.40 (d, J = 6.1 Hz,2H), 1.20-1.08 (m, 5H), 0.72 (t, J = 7.3 Hz, 3H) (2 exchangeable protonswere not observed) 1.20 A 561.3 A 179

4′-((6-butyl-2,4- dihydroxy-5-(2,3,4,5- tetrahydro-1H- benzo[b]azepin-1-yl)pyridin-3- yl)sulfonyl)-N,N- dimethyl-[1,1′- biphenyl]-2-carboxamide¹H NMR (500 MHz, DMSO-d6) δ 8.10 (d, J = 8.1 Hz, 2H), 7.66-7.50 (m, 5H),7.39 (d, J = 7.2 Hz, 1H), 7.10 (d, J = 7.4 Hz, 1H), 6.99 (t, J = 7.6 Hz,1H), 6.84- 6.73 (m, 1H), 6.51 (d, J = 8.0 Hz, 1H), 3.31 (d, J = 12.6 Hz,2H), 2.89 (s, 4H), 2.51-2.50 (m, 6H), 2.34-1.90 (m, 2H), 1.78 (br. s.,2H), 1.49-1.28 (m, 2H), 1.13 (br. s., 2H), 0.69 (t, J = 6.7 Hz, 3H) (2exchangeable protons not observed) 1.26 A 600.4 B 180

6-butyl-3-((4-(2-fluoro- 3-methylpyridin-4- yl)phenyl)sulfonyl)-5-(2,3,4,5-tetrahydro-1H- benzo[b]azepin-1- yl)pyridine-2,4-diol ¹H NMR(500 MHz, DMSO-d6) δ 8.16 (d, J = 7.5 Hz, 2H), 7.67 (d, J = 7.2 Hz, 2H),7.30 (d, J = 4.3 Hz, 2H), 7.07 (d, J = 6.8 Hz, 1H), 6.95 (br. s., 1H),6.74 (br. s., 1H), 6.49 (d, J = 7.7 Hz, 1H), 3.51 (br. s., 2H), 2.28(br. s., 2H), 2.16 (s, 3H), 1.91 (br. s., 1H), 1.84-1.61 (m, 2H),1.49-1.28 (m, 2H), 1.25-1.05 (m, 4H), 0.69 (t, J = 6.6 Hz, 3H) (2exchangeable protons not observed) 1.30 A 562.3 A 181

4′-((6-butyl-5-((3- cyanophenyl)(ethyl)a- mino)-2,4- dihdyroxypyridin-3-yl)sulfonyl)-[1,1′- biphenyl]-2-carboxamide ¹H NMR (500 MHz, DMSO-d6) δ8.18- 7.86 (m, 2H), 7.82-7.66 (m, 1H), 7.63- 7.19 (m, 7H), 7.04-6.63 (m,2H), 2.29- 2.09 (m, 2H), 1.44-1.31 (m, 2H), 1.25- 1.07 (m, 5H),1.06-0.95 (m, 2H), 0.71 (br t, J = 7.2 Hz, 3H) (4 exchangeable protonsnot observed) 1.53 A 571.2 A 182

4′-((6-butyl-5-((3,5- dimethyphenyl)(ethyl)a- mino)-2,4-dihydroxypyridin-3- yl)sulfonyl)-N-methyl- [1,1′-biphenyl]-2-carboxamide¹H NMR (500 MHz, DMSO-d6) δ 8.22 (br. s., 1H), 7.97 (d, J = 7.7 Hz, 2H),7.53 (d, J = 7.1 Hz, 3H), 7.48-7.40 (m, 3H), 6.28 (br. s., 1H), 6.15(br. s., 2H), 2.59 (d, J = 4.4 Hz, 3H), 2.35-2.22 (m, 2H), 2.17-2.10 (m,6H), 1.47-1.37 (m, 2H), 1.23 (s, 2H), 1.20-1.13 (m, 2H), 1.10 (t, J =6.9 Hz, 3H), 0.73 (t, J = 7.3 Hz, 3H) (2 exchangeable protons notobserved) 1.18 A 588.3 A 183

6-butyl-5-((3,5-di- methylphenyl)(ethyl)a- mino)-3-((4-(2-methylpyridin-3- yl)phenyl)sulfonyl)pyri- dine-2,4-diol ¹H NMR (500 MHz,DMSO-d6) δ 8.49 (br. s., 1H), 8.06 (d, J = 7.6 Hz, 2H), 7.72- 7.56 (m,3H), 7.35 (br. s., 1H), 6.30 (br. s., 1H), 6.15 (br. s., 2H), 3.65-3.58(m, 1H), 3.52-3.36 (m, 1H), 2.43 (br. s., 3H), 2.38-2.21 (m, 2H), 2.14(br. s., 6H), 1.41 (d, J = 7.3 Hz, 2H), 1.22-1.06 (m, 5H), 0.73 (t, J =7.2 Hz, 3H) (2 exchangeable protons not observed) 0.97 A 546.3 B 184

4′-((6-butyl-2,4- dihydroxy-5-(2,3,4,5- tetrahydro-1H- benzo[b]azepin-1-yl)pyridin-3- yl)sulfonyl)-N-methyl- [1,1′-biphenyl]-2-carboxamide ¹HNMR (500 MHz, DMSO-d6) δ 8.09 (br. s., 2H), 7.96 (d, J = 7.6 Hz, 2H),7.56- 7.49 (m, 1H), 7.47-7.37 (m, 4H), 6.98 (d, J = 7.0 Hz, 1H),6.86-6.77 (m, 1H), 6.64 (t, J = 7.0 Hz, 1H), 6.37 (d, J = 7.9 Hz, 1H),3.25 (d, J = 12.5 Hz, 2H), 2.87- 2.65 (m, 2H), 2.58 (d, J = 4.0 Hz, 3H),2.36-2.13 (m, 2H), 2.04-1.84 (m, 2H), 1.75-1.54 (m, 2H), 1.41-1.24 (m,2H), 1.11 (br. s., 2H), 0.67 (t, J = 6.6 Hz, 3H) (2 exchangeable protonsnot observed) 1.26 A 586.3 B 185

4′-((6-butyl-5-((3- cyanophenyl)(ethyl)a- mino)-2,4- dihydroxypyridin-3-yl)sulfonyl)-N-methyl- [1,1′-biphenyl]-2-carboxamide ¹H NMR (500 MHz,DMSO-d6) δ 8.06 (d, J = 4.6 Hz, 1H), 7.87 (d, J = 7.9 Hz, 2H), 7.49 (d,J = 7.6 Hz, 1H), 7.45-7.35 (m, 5H), 7.23 (t, J = 7.9 Hz, 1H), 6.90 (d, J= 7.3 Hz, 1H), 6.76 (d, J = 8.9 Hz, 1H), 6.66 (br. s., 1H), 3.46-3.27(m, 2H), 2.50-2.50 (m, 3H), 2.27-2.04 (m, 2H), 1.34 (d, J = 6.7 Hz, 2H),1.16-1.08 (m, 2H), 1.02 (t, J = 7.0 Hz, 3H), 0.68 (t, J = 7.2 Hz, 3H) (2exchangeable protons not observed) 1.14 A 585.3 A 186

4′-((6-butyl-5-((3- cyanophenyl)(ethyl)a- mino)-2,4- dihydroxypyridin-3-yl)sulfonyl)-N,N- dimethyl-[1,1′- biphenyl]-2-carboxamide ¹H NMR (500MHz, DMSO-d6) δ 8.04 (d, J = 7.6 Hz, 2H), 7.61-7.48 (m, 5H), 7.40-7.30(m, 2H), 7.07 (d, J = 6.4 Hz, 1H), 6.99 (br. s., 1H), 6.89 (d, J = 7.0Hz, 1H), 3.61-3.48 (m, 2H), 2.51 (br. s., 6H), 2.42-2.21 (m, 2H),1.46-1.31 (m, 2H), 1.17-1.09 (m, 5H), 0.70 (t, J = 7.3 Hz, 3H) (2exchangeable protons not observed) 1.16 A 599.4 A 187

5-(ethyl(phenyl)amino)- 3-((4-(3-methylpyridin- 4-yl)phenyl)sulfonyl)-6-(2-methylthiazol-5- yl)pyridine-2,4-diol ¹H NMR (500 MHz, DMSO-d6) δ8.75- 8.58 (m, 2H), 8.18 (d, J = 8.2 Hz, 2H), 7.79 (s, 1H), 7.75 (d, J =7.9 Hz, 2H), 7.55 (d, J = 4.6 Hz, 1H), 7.22-7.15 (m, 2H), 6.79-6.64 (m,3H), 3.56 (br. s., 2H), 2.67 (s, 3H), 2.32 (s, 3H), 1.05 (t, J = 7.0 Hz,3H) (2 exchangeable protons not observed) 1.00 A 559.3 A 188

4′-((5- (ethyl(phenyl)amino)- 2,4-dihydroxy-6-(2- methylthiazol-5-yl)pyridin-3- yl)suflonyl)-N-methyl- [1,1′-biphenyl]-3-carboxamide ¹HNMR (500 MHz, DMSO-d6) δ 8.60 (d, J = 4.3 Hz, 1H), 8.18 (s, 1H), 8.13(d, J = 8.2 Hz, 2H), 7.98 (d, J = 7.9 Hz, 2H), 7.90 (t, J = 6.7 Hz, 2H),7.78 (s, 1H), 7.61 (t, J = 7.6 Hz, 1H), 7.18 (t, J = 7.8 Hz, 2H),6.74-6.64 (m, 3H), 3.48 (br. s., 2H), 2.89 (s, 3H), 2.82 (d, J = 4.3 Hz,3H), 1.04 (t, J = 7.2 Hz, 3H) (2 exchangeable protons not observed) 1.15A 601.4 A 189

N-cyclopropyl-4′-((5- (ethyl(phenyl)amino)- 2,4-dihydroxy-6-(2-methylthiazol-5- yl)pyridin-3- yl)sulfonyl)-[1,1′-biphenyl]-2-carboxamide ¹H NMR (500 MHz, DMSO-d6) δ 8.01 (d, J = 3.7 Hz,1H), 7.86 (d, J = 7.9 Hz, 1H), 7.75 (s, 1H), 7.59 (s, 1H), 7.38- 7.32(m, 3H), 7.31-7.21 (m, 3H), 6.98 (t, J = 7.6 Hz, 2H), 6.55-6.45 (m, 3H),3.34-3.32 (m, 2H), 2.70 (s, 3H), 2.42- 2.37 (m, 1H), 0.85 (t, J = 7.0Hz, 3H), 0.30 (d, J = 7.3 Hz, 2H), 0.00 (br. s., 2H) (2 exchangeableprotons not observed) 1.18 A 627.3 A 190

5-(ethyl(phenyl)amino)- 3-((4-(6-fluoro-2- methylpyridin-3-yl)phenyl)sulfonyl)-6- (2-methylthiazol-5- yl)pyridine-2,4-diol ¹H NMR(500 MHz, DMSO-d6) δ 8.11 (d, J = 7.9 Hz, 2H), 7.89 (t, J = 8.1 Hz, 1H),7.77 (s, 1H), 7.66 (d, J = 7.6 Hz, 2H), 7.17 (t, J = 7.6 Hz, 2H), 7.12(d, J = 6.1 Hz, 1H) ,6.73-6.65 (m, 3H), 3.57- 3.47 (m, 2H), 2.67 (s,3H), 2.39 (s, 3H), 1.03 (t, J = 7.0 Hz, 3H) (2 exchangeable protons notobserved) 1.24 A 577.3 A 191

5-(ethyl(phenyl)amino)- 3-((4-(2-fluoro-3- methylpyridin-4-yl)phenyl)sulfonyl)-6- (2-methylthiazol-5- yl)pyridine-2,4-diol ¹H NMR(500 MHz, DMSO-d6) δ 8.12 (d, J = 4.9 Hz, 1H), 8.03 (d, J = 7.9 Hz, 2H),7.63 (s, 1H), 7.54 (d, J = 7.9 Hz, 2H), 7.25 (d, J = 4.9 Hz, 1H), 7.08(t, J = 7.6 Hz, 2H), 6.59 (d, J = 8.2 Hz, 3H), 3.43 (br. s., 2H), 2.90(s, 3H), 2.15 (s, 3H), 0.96 (t, J = 7.2 Hz, 3H) (2 exchangeable protonsnot observed) 1.24 A 577.3 A 192

4′-((5- (ethyl(phenyl)amino)- 2,4-dihydroxy-6-(2- methylthiazol-5-yl)pyridin-3- yl)suflonyl)-N-methyl- [1,1′-biphenyl]-2-carboxamide ¹HNMR (500 MHz, DMSO-d6) δ 8.20 (d, J = 4.6 Hz, 1H), 8.05 (d, J = 8.2 Hz,2H), 7.79 (s, 1H), 7.61-7.52 (m, 3H), 7.50-7.40 (m, 3H), 7.24-7.12 (m,2H), 6.75-6.64 (m, 3H), 3.53 (br. s., 2H), 2.66 (s, 3H), 2.60 (d, J =4.6 Hz, 3H), 1.04 (t, J = 7.2 Hz, 3H) (2 exchangeable protons notobserved) 1.14 A 601.3 A 193

6-butyl-3-((4-(2-fluoro- 3-methypyridin-4- yl)phenyl)sulfonyl)-5-(methyl(o- tolyl)amino)pyridine-2,4-diol ¹H NMR (500 MHz, DMSO-d6) δ8.17- 8.05 (m, 2H), 7.63 (d, J = 7.0 Hz, 2H), 7.25 (br. s., 1H), 7.12(br. s., 2H), 6.63 (br. s., 1H), 6.53 (d, J = 7.0 Hz, 2H), 3.74 (br. s.,3H), 2.39-2.21 (m, 2H), 2.14 (br. s., 3H), 1.38 (br. s., 2H), 1.19-1.07(m, 5H), 0.70 (t, J = 7.3 Hz, 3H) (2 exchangeable protons not observed)1.29 A 536.3 A 194

6-butyl-5-(methyl(o- tolyl)amino)-3-((4-(2- methylpyridin-3-yl)phenyl)sulfonyl)pyri- dine-2,4-diol ¹H NMR (500 MHz, DMSO-d6) δ 8.10-7.86 (m, 2H), 7.68-7.55 (m, 1H), 7.42 (br. s., 2H), 7.32 (br. s.., 1H),7.01 (br. s., 2H), 6.54-6.34 (m, 3H), 3.67 (br. s., 3H), 2.55 (s, 3H),2.17 (br. s., 2H), 1.38 (br. s., 2H), 1.18-0.97 (m, 5H), 0.72 (t, J =7.0 Hz, 3H) (2 exchangeable protons not observed) 1.06 A 518.4 B 195

4′-((6-butyl-2,4- dihydroxy-5-(methyl(o- tolyl)amino)pyridin-3-yl)sulfonyl)-[1,1′- biphenyl]-2-carboxamide ¹H NMR (500 MHz, DMSO-d6) δ7.95 (d, J = 7.6 Hz, 2H), 7.78 (br. s., 1H), 7.57- 7.43 (m, 5H), 7.39(d, J = 7.0 Hz, 1H), 7.31 (br. s., 1H), 7.09 (br. s., 2H), 6.58 (br. s.,1H), 6.50 (d, J = 7.3 Hz, 2H), 3.68 (br. s., 3H), 2.36-2.13 (m, 2H),1.47- 1.32 (m, 2H), 1.23-1.04 (m, 4H), 0.71 (t, J = 7.2 Hz, 3H) (2exchangeable protons not observed) 1.19 A 546.4 A 196

4′-((6-butyl-2,4- dihydroxy-5-(methyl(o- tolyl)amino)pyridin-3-yl)sulfonyl)-N,N- dimethyl-[1,1′- biphenyl]-2-carboxamide ¹H NMR (500MHz, DMSO-d6) δ 7.61- 7.49 (m, 6H), 7.37 (d, J = 7.4 Hz, 1H), 7.20-7.12(m, 2H), 6.67 (br. s., 1H), 6.56 (d, J = 7.7 Hz, 2H), 3.64-3.61 (m, 3H),2.77 (s, 3H), 2.51 (br. s., 6H), 2.40- 2.21 (m, 2H), 1.38 (br. s., 2H),1.14 (d, J = 5.9 Hz, 5H), 0.70 (t, J = 7.2 Hz, 3H) (2 exchangeableprotons not observed) 1.22 A 574.4 A 198

6-butyl-3-((4-(6-fluoro- 2-methylpyridin-3- yl)phenyl)sulfonyl)-5-(methyl(o- tolyl)amino)pyridine-2,4-diol ¹H NMR (500 MHz, DMSO-d6) δ8.07 (br. s., 1H), 7.88 (t, J = 8.1 Hz, 1H), 7.65 (d, J = 7.6 Hz, 2H),7.20-7.06 (m, 3H), 6.71-6.63 (m, 1H), 6.57 (d, J = 7.9 Hz, 2H), 2.55 (s,3H), 2.42-2.24 (m, 5H), 1.42 (br. s., 2H), 1.21-1.09 (m, 5H), 0.72 (t, J= 7.2 Hz, 3H) (2 exchangeable protons not observed) 1.29 A 536.3 B 203

6-butyl-5-(methyl(o- tolyl)amino)-3-((4-(3- methypyridin-4-yl)phenyl)sulfonyl)pyri- dine-2,4-diol ¹H NMR (500 MHz, DMSO-d6) δ 8.52(br. s., 1H), 8.46 (br. s., 1H), 8.04 (br. s., 1H), 7.56 (d, J = 7.3 Hz,2H), 7.27 (d, J = 4.0 Hz, 1H), 7.08 (t, J = 7.3 Hz, 2H), 6.58 (t, J =6.6 Hz, 1H), 6.50 (d, J = 7.9 Hz, 2H), 2.51 (br. s., 6H), 2.24 (s, 3H),1.45-1.35 (m, 2H), 1.21-1.13 (m, 2H), 1.09 (t, J = 6.9 Hz, 2H), 0.72 (t,J = 7.2 Hz, 3H) (2 exchangeable protons not observed) 1.07 A 518.4 A 206

4′-((6-butyl-2,4- dihydroxy-5-(methyl(o- tolyl)amino)pyridin-3-yl)sulfonyl)-N-methyl- [1,1′-biphenyl]-2-carboxamide ¹H NMR (500 MHz,DMSO-d6) δ 7.94 (d, J = 7.9 Hz, 2H), 7.58-7.36 (m, 5H), 7.08 (t, J = 7.5Hz, 2H), 6.58 (br. s., 1H), 6.50 (d, J = 7.9 Hz, 2H), 3.56 (d, J = 10.4Hz, 3H), 2.58 (d, J = 4.6 Hz, 3H), 2.30- 2.08 (m, 2H), 1.44-1.34 (m,2H), 1.21- 1.06 (m, 5H), 0.71 (t, J = 7.3 Hz, 3H) (3 exchangeableprotons not observed) 1.22 A 560.4 A 208

4′-((6-butyl-2,4- dihydroxy-5-(methyl(o- tolyl)amino)pyridin-3-yl)sulfonyl)-N- cyclopropyl-[1,1′- biphenyl]-2-carboxamide ¹H NMR (500MHz, DMSO-d6) δ 7.78 (d, J = 7.9 Hz, 2H), 7.36-7.20 (m, 5H), 6.91 (t, J= 7.5 Hz, 2H), 6.41 (t, J = 6.7 Hz, 1H), 6.33 (d, J = 7.9 Hz, 2H), 2.39(t, J = 3.7 Hz, 1H), 2.31-2.28 (m, 3H), 2.15- 1.97 (m, 2H), 1.27-1.15(m, 2H), 1.02- 0.87 (m, 5H), 0.52 (t, J = 7.2 Hz, 3H), 0.30 (d, J = 7.3Hz, 2H), 0.00 (br. s., 2H) (3 exchangeable protons not observed) 1.21 A586.4 A 210

4′-((5-((3-cyano- phenyl)(ethyl)amino)- 2,4-dihydroxy-6-(1-methyl-1H-pyrazol-3- yl)pyridin-3- yl)sulfonyl)-N,N- dimethyl-[1,1′-biphenyl]-2-carboxamide ¹H NMR (500 MHz, DMSO-d6) δ 7.87 (br. s., 2H),7.64 (br. s., 1H), 7.51 (d, J = 7.0 Hz, 1H), 7.46 (br. s., 2H), 7.39 (d,J = 6.7 Hz, 2H), 7.33 (d, J = 7.0 Hz, 1H), 7.22 (br. s., 1H), 6.92 (d, J= 6.4 Hz, 1H), 6.76 (br. s., 2H), 6.15 (br. s., 1H), 3.84 (br. s., 2H),3.60 (br. s., 3H), 2.72 (br. s., 3H), 2.39 (br. s., 3H), 0.91 (br. s.,3H) (2 exchangeable protons not observed) 1.12 A 623.4 A 211

3-(ethyl(5-((4-(2-fluoro- 3-methylpyridin-4- yl)phenyl)sulfonyl)-4,6-dihydroxy-2-(1-methyl- 1H-pyrazol-3- yl)pyridin-3- yl)amino)benzonitrile¹H NMR (500 MHz, DMSO-d6) δ 8.10 (d, J = 4.7 Hz, 1H), 7.99 (d, J = 7.2Hz, 2H), 7.68 (br. s., 1H), 7.51 (d, J = 6.7 Hz, 2H), 7.23 (br. s., 2H),6.95 (d, J = 6.9 Hz, 1H), 6.80 (br. s., 1H), 6.18 (br. s., 1H), 3.85 (s,2H), 3.59-3.55 (m, 3H), 2.12 (br. s., 3H), 0.92 (br. s., 3H) (2exchangeable protons not observed) 1.13 A 585.3 A 212

3-((4,6-dihydroxy-2-(1- methyl-1H-pyrazol-3- yl)-5-((4-(3-methylpyridin-4- yl)phenyl)sulfonyl)pyri- din-3-yl)(ethyl)amino)benzonitrile ¹H NMR (500 MHz, DMSO-d6) δ 8.72- 8.53 (m,2H), 8.16 (d, J = 8.0 Hz, 2H), 7.79-7.67 (m, 3H), 7.41 (br. s., 1H),7.34 (t, J = 8.0 Hz, 1H), 7.28-7.15 (m, 1H), 7.13-7.04 (m, 3H), 6.96 (d,J = 7.9 Hz, 1H), 6.28 (s, 1H), 3.87 (s, 3H), 3.58 (br. s., 2H), 2.28 (s,3H), 1.02 (t, J = 6.9 Hz, 3H) (2 exchangeable protons not observed).0.89 A 567.4 A 213

3-(ethyl(5-((4-(6-fluoro- 2-methylpyridin-3- yl)phenyl)sulfonyl)-4,6-dihydroxy-2-(1-methyl- 1H-pyrazol-3- yl)pyridin-3- yl)amino)benzonitrile¹H NMR (500 MHz, DMSO-d6) δ 8.10 (d, J = 6.8 Hz, 2H), 7.87 (br. s., 1H),7.74 (br. s., 1H), 7.63 (br. s., 2H), 7.31 (br. s., 1H), 7.16-7.01 (m,3H), 6.93 (br. s., 1H), 6.27 (br. s., 1H), 3.87 (br. s., 2H), 3.52 (br.s., 3H), 2.38 (br. s., 3H), 1.01 (br. s., 3H) (2 exchangeable protonsnot observed) 1.10 A 585.4 A 214

4′-((5-((3- cyanophenyl)(ethyl)ami- no)-2,4-dihydroxy-6-(1-methyl-1H-pyrazol-3- yl)pyridin-3- yl)sulfonyl)-N-methyl-[1,1′-biphenyl]-2-carboxamide ¹H NMR (500 MHz, DMSO-d6) δ 8.14 (br. s.,1H), 7.88 (d, J = 7.9 Hz, 2H), 7.67 (s, 1H), 7.54-7.48 (m, 1H),7.45-7.36 (m, 5H), 7.24 (t, J = 7.9 Hz, 1H), 6.96 (d, J = 7.3 Hz, 1H),6.86-6.76 (m, 2H), 6.18 (s, 1H), 3.86 (s, 2H), 3.53 (d, J = 2.8 Hz, 3H),2.57 (d, J = 4.5 Hz, Hz, 3H), 0.94 (t, J = 7.1 Hz, 3H) (3 exchangeableprotons were not observed) 1.05 A 608.4 A 215

4′-((5-((3- cyanophenyl)(ethyl)ami- no)-2,4-dihydroxy-6-(1-methyl-1H-pyrazol-3- yl)pyridin-3- yl)sulfonyl)-3-fluoro-[1,1′-biphenyl]-2-carboxamide ¹H NMR (500 MHz, DMSO-d6) δ 8.00 (br. s.,1H), 7.89 (d, J = 7.7 Hz, 2H), 7.67 (br. s., 1H), 7.59 (br. s., 1H),7.54-7.46 (m, 3H), 7.29 (t, J = 8.8 Hz, 1H), 7.25- 7.20 (m, 2H), 6.95(d, J = 7.3 Hz, 1H), 6.87-6.75 (m, 2H), 6.17 (s, 1H), 3.86 (s, 3H),3.47-3.45 (m, 2H), 0.94 (t, J = 6.9 Hz, 3H) (2 exchangeable protons notobserved) 1.00 A 613.4 A 216

4′-((5-((3- cyanophenyl)(ethyl)ami- no)-2,4-dihydroxy-6-(1-methyl-1H-pyrazol-3- yl)pyridin-3- yl)sulfonyl)-[1,1′-biphenyl]-2-carboxamide ¹H NMR (500 MHz, DMSO-d6) δ 8.01 (d, J = 7.5 Hz,2H), 7.83 (br. s., 1H), 7.76- 7.65 (m, 1H), 7.58 (d, J = 6.7 Hz, 2H),7.54-7.43 (m, 4H), 7.43-7.24 (m, 3H), 7.08-6.84 (m, 2H), 6.25 (br. s.,1H), 3.87 (br. s., 2H), 3.66-3.60 (m, 3H), 1.00 (br. s., 3H) (2exchangeable protons not observed) 1.05 A 595.4 A 217

3-((4,6-dihydroxy-2-(1- methyl-1H-pyrazol-3- yl)-5-((4-(2-methylpyridin-3- ylphenyl)sulfonyl)pyri- din-3-yl)(ethyl)amino)benzonitrile ¹H NMR (500 MHz, DMSO-d6) δ 8.47 (d, J =4.4 Hz, 1H), 7.99 (d, J = 7.5 Hz, 2H), 7.68 (br. s., 1H), 7.63 (d, J =6.7 Hz, 1H), 7.51 (d, J = 7.2 Hz, 2H), 7.37-7.30 (m, 1H), 7.29-7.21 (m,1H), 6.97 (d, J = 7.1 Hz, 1H), 6.85 (br. s., 2H), 6.19 (s, 1H), 3.85(br. s., 2H), 3.73-3.70 (m, 3H), 2.40 (br. s., 3H), 0.94 (br. s., 3H) (2exchangeable protons not observed) 0.87 A 567.4 A 218

4′-((5-((3- cyanophenyl)(ethyl)ami- no)-2,4-dihydroxy-6-(1-methyl-1H-pyrazol-3- yl)pyridin-3- y)sulfonyl)-N- cyclopropyl-[1,1′-biphenyl]-2-carboxamide ¹H NMR (500 MHz, DMSO-d6) δ 8.05 (br. s., 1H),7.87 (d, J = 8.3 Hz, 2H), 7.54 (br. s., 1H), 7.40-7.32 (m, 3H), 7.30-7.22 (m, 3H), 7.15 (t, J = 8.1 Hz, 1H), 6.91 (d, J = 6.7 Hz, 2H), 6.76(d, J = 8.3 Hz, 1H), 6.09 (s, 1H), 3.67 (s, 3H), 3.43- 3.38 (m, 2H),1.00-0.89 (m, 1H), 0.83 (t, J = 7.2 Hz, 3H), 0.31 (d, J = 6.0 Hz, 2H),0.00 (br. s., 2H) (2 exchangeable protons not observed) 1.06 A 635.4 A

Example 199.(3-(5-chloropyridin-2-yl)pyrrolidin-1-yl)(5-(ethyl(phenyl)amino)-2,4-dihydroxy-6-(1-methyl-1H-pyrazol-3-yl)pyridin-3-yl)methanone

Example 199A. tert-butyl3-(5-chloropyridin-2-yl)-2,5-dihydro-1H-pyrrole-1-carboxylate

A mixture of tert-butyl3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,5-dihydro-1H-pyrrole-1-carboxylate(106 mg, 0.360 mmol), 2-bromo-5-chloropyridine (76 mg, 0.40 mmol),cesium carbonate (350 mg, 1.10 mmol) and PdCl₂(dppf)-CH₂Cl₂ (18 mg,0.022 mmol) in dioxane (2.4 mL) and water (0.5 mL) was degassed andheated at 90° C. for 14 h. The mixture was diluted with EtOAc, washedwith brine, dried over sodium sulfate, filtered and concentrated underreduced pressure. The residue was subjected to silica gel chromatographyeluting with 0-100% EtOAc/hexane to give Example 199A (50 mg, 0.18 mmol,50% yield) as a yellow solid. ¹H NMR (400 MHz, CHLOROFORM-d) δ 8.62-8.41(m, 1H), 7.82-7.57 (m, 1H), 7.40-7.16 (m, 1H), 6.60-6.32 (m, 1H),4.60-4.49 (m, 2H), 4.41-4.27 (m, 2H), 1.52-1.45 (m, 9H).

Example 199B. tert-butyl3-(5-chloropyridin-2-yl)pyrrolidine-1-carboxylate

A mixture of Example 199A (530 mg, 1.90 mmol) and 5% Rh/C (390 mg, 0.190mmol) in EtOH (8 mL) was stirred under hydrogen atmosphere (balloon) for4 h. The mixture was filtered through Celite and concentrated underreduced pressure. The residue was purified using silica gelchromatography eluting with 0-100% EtOAc/hexane, followed by chiral SFCpreparative HPLC (column: Chiralpak IC, 30×250 mm, 5 micron; mobilephase: 10% IPA/0.1% DEA/90% CO₂; flow condition: 85 mL/min, 150 bar, 40°C.; wavelength: 220 nm) to give Example 199B (designated as isomer 1,110 mg, 21% yield). Peak 1 retention time=11.87 (Chiralpak IC, 4.6×250mm, 5 micron; mobile phase: 10% IPA/0.1% DEA/90% CO₂; flow condition:2.0 mL/min, 150 bar, 40° C.; wavelength: 220 nm. LCMS (Method B) Rt=0.96min, m/z=283.2 (M+H). ¹H NMR (400 MHz, CHLOROFORM-d) δ 8.52 (d, J=2.2Hz, 1H), 7.64-7.56 (m, 1H), 7.14 (d, J=8.4 Hz, 1H), 3.97-3.29 (m, 5H),2.34-2.05 (m, 2H), 1.50-1.44 (m, 9H).

Example 199C. tert-butyl3-(5-chloropyridin-2-yl)-2,5-dihydro-1H-pyrrole-1-carboxylate

Example 199B (110 mg, 0.38 mmol) and 4N HCl/dioxane (1.0 mL, 4.0 mmol)were stirred at rt for 5 h. The mixture was diluted with diethyl ether,and the solid was collected by filtration to give Example 199C (89 mg,0.348 mmol, 91% yield) as a white solid. LCMS (Method B) Rt=0.47 min,m/z=183.1 (M+H). ¹H NMR (500 MHz, DMSO-d6) δ 7.79 (d, J=2.5 Hz, 1H),7.24-6.97 (m, 1H), 6.83-6.56 (m, 1H), 3.01 (s, 1H), 2.83 (s, 2H),2.77-2.67 (m, 1H), 2.54 (br. s., 2H), 1.85-1.57 (m, 1H), 1.53-1.14 (m,1H).

Example 199.(6-butyl-5-(2,6-dimethoxyphenyl)-2,4-dihydroxypyridin-3-yl)(3-(5-chloropyridin-2-yl)pyrrolidin-1-yl)methanone

Example 199 was prepared from Example 199C using the method describedfor Example 1. LCMS (Method A) Rt=1.13 min, m/z=519.3 (M+H). ¹H NMR (500MHz, DMSO-d₆) δ 8.56 (br. s., 1H), 7.86 (br. s., 1H), 7.68 (br. s., 1H),7.44 (br. s., 1H), 7.12 (d, J=6.7 Hz, 2H), 6.60 (d, J=8.2 Hz, 3H), 6.23(br. s., 1H), 3.96-3.81 (m, 4H), 3.46 (br. s., 3H), 3.18 (br. s., 1H),2.35-2.01 (m, 4H), 1.07-0.93 (m, 3H) (2 exchangeable protons notobserved). Human APJ cAMP EC₅₀ Potency range A.

The compounds listed in the table below were synthesized using methodsanalogous to Example 199.

TABLE 2 LC/MS hAPJ Rt cAMP (min) EC₅₀ Ex Method Potency # StructureChiral Amine Name ¹H NMR M + H range 197

(3-(3,5-difluoropyridin-2- yl)pyrrolidin-1-yl)(5-(ethyl(phenyl)amino)-2,4- dihydroxy-6-(1-methyl-1H-pyrazol-3-yl)pyridin-3- yl)methanone ¹H NMR (500 MHz, DMSO-d₆) δ 8.45(br. s., 2H), 7.87 (br. s., 1H), 7.69 (br. s., 1H), 7.14 (br. s., 2H),6.73-6.52 (m, 3H), 6.20 (br. s., 1H), 3.86 (br. s., 5H), 3.67-3.57 (m,2H), 3.53-3.31 (m, 2H), 3.26 (br. s., 1H), 2.31-2.03 (m, 2H), 0.98 (br.s., 3H) (2 exchangeable protons not observed) 1.15 A 521.4 A 200

(3-(5-chloropyridin-2- yl)pyrrolidin-1-yl)(5- (ethyl(phenyl)amino)-2,4-dihydroxy-6-(1-methyl-1H- pyrazol-3-yl)pyridin-3- yl)methanone ¹H NMR(500 MHz, DMSO-d₆) δ 8.56 (br. s., 1H), 7.86 (br. s., 1H), 7.68 (br. s.,1H), 7.44 (br. s., 1H), 7.12 (d, J = 6.7 Hz, 2H), 6.60 (d, J = 8.2 Hz,3H), 6.23 (br. s., 1H), 3.96-3.81 (m, 4H), 3.46 (br. s., 3H), 3.18 (br.s., 1H), 2.35- 2.01 (m, 4H), 1.07-0.93 (m, 3H) (2 exchangeable protonsnot observed) 1.14 A 519.4 A 201

(3-(2,4- difluorophenyl)pyrrolidin-1- yl)(5-(ethyl(phenyl)amino)-2,4-dihydroxy-6-(1-methyl- 1H-pyrazol-3-yl)pyridin-3- yl)methanone ¹HNMR (500 MHz, DMSO-d₆) δ 7.69 (br. s., 1H), 7.47 (d, J = 7.0 Hz, 1H),7.25-7.01 (m, 4H), 6.69-6.56 (m, 3H), 6.22 (br. s., 1H), 3.87 (br. s.,7H), 2.54 (s, 3H), 2.31-1.97 (m, 2H), 1.03- 0.94 (m, 3H) (2 exchangeableprotons not observed) 1.19 A 520.4 A 202

(5-(ethyl(phenyl)amino)- 2,4-dihydroxy-6-(1-methyl-1H-pyrazol-3-yl)pyridin-3- yl)(3-(2- fluorophenyl)pyrrolidin-1-yl)methanone ¹H NMR (500 MHz, DMSO-d₆) δ 7.70 (br. s., 1H), 7.45-7.26(m, 2H), 7.22- 7.10 (m, 4H), 6.69-6.56 (m, 3H), 6.23 (br. s., 1H),4.00-3.11 (m, 7H), 2.55 (s, 3H), 2.33-1.93 (m, 2H), 1.07- 0.92 (m, 3H)(2 exchangeable protons not observed) 1.19 A 502.4 A 204

(3-(5-chloro-3- fluoropyridin-2- yl)pyrrolidin-1-yl)(5-(ethyl(phenyl)amino)-2,4- dihydroxy-6-(1-methyl-1H-pyrazol-3-yl)pyridin-3- yl)methanone ¹H NMR (500 MHz, DMSO-d₆) δ 8.45(br. s., 1H), 8.00 (d, J = 9.8 Hz, 1H), 7.67 (s, 1H), 7.12 (d, J = 6.7Hz, 2H), 6.69-6.53 (m, 3H), 6.21 (br. s., 1H), 3.86 (s, 3H), 3.71-3.55(m, 3H), 3.54- 3.34 (m, 2H), 2.49-2.46 (m, 2H), 2.26 (br. s., 2H), 0.98(br. s., 3H) (2 exchangeable protons not observed) 1.24 A 537.0 A 205

(5-(ethyl(phenyl)amino)- 2,4-dihydroxy-6-(1-methyl-1H-pyrazol-3-yl)pyridin-3- yl)(3-(2- fluorophenyl)pyrrolidin-1-yl)methanone ¹H NMR (500 MHz, DMSO-d₆) δ 7.70 (br. s., 1H), 7.45-7.26(m, 2H), 7.22- 7.10 (m ,4H), 6.69-6.56 (m, 3H), 6.23 (br. s., 1H),4.00-3.11 (m, 7H), 2.55 (s, 3H), 2.33-1.93 (m, 2H), 1.07- 0.92 (m, 3H)(2 exchangeable protons not observed) 1.17 A 502.4 A 207

(3-(2,4- difluorophenyl)pyrrolidin-1- yl)(5-(ethyl(phenyl)amino)-2,4-dihydroxy-6-(1-methyl- 1H-pyrazol-3-yl)pyridin-3- yl)methanone ¹HNMR (500 MHz, DMSO-d₆) δ 7.69 (br. s., 1H), 7.47 (d, J = 7.0 Hz, 1H),7.25-7.01 (m, 4H), 6.69-6.56 (m, 3H), 6.22 (br. s., 1H), 3.87 (br. s.,7H), 2.54 (s, 3H), 2.31-1.97 (m, 2H), 1.03- 0.94 (m, 3H) (2 exchangeableprotons not observed) 1.20 A 520.4 A 209

(3-(2,4- difluorophenyl)pyrrolidin-1- yl)(2,4-dihydroxy-5-(isopropyl(phenyl)amino)- 6-(1-methyl-1H-pyrazol-3-yl)pyridin-3-yl)methanone 1H NMR (500 MHz, DMSO-d6) Shift 7.85 (br s,1H), 7.62 (br s, 1H), 7.50- 7.28 (m, 2H), 7.18 (br d, J = 7.3 Hz, 1H),7.02 (br s, 2H), 6.61-6.46 (m, 2H), 6.18 (br s, 1H), 4.59-4.38 (m, 1H),3.49 (br d, J = 10.1 Hz, 6H), 3.22- 3.14 (m, 1H), 2.89 (s, 3H),2.23-2.12 (m, 2H), 2.05-1.90 (m, 4H) (2 exchangeable protons notobserved) 1.40 A 534.2 A

1. A compound of Formula (I):

or a stereoisomer, an enantiomer, a diastereomer, a tautomer, or apharmaceutically acceptable salt thereof, wherein R¹ is independentlyselected from

Ring A is independently selected from

Ring B is independently selected from aryl and heterocyclyl comprisingcarbon atoms and 1-4 heteroatoms selected from N, NR^(3a), O, and S,each substituted with 1-3 R³ and 1-2 R⁵; provided R³ and R⁵ are not bothH; R² is independently selected from C₁₋₅ alkyl substituted with 0-3R^(e); C₂₋₅ alkenyl substituted with 0-3 R^(e), aryl substituted with0-3 R^(e), heterocyclyl substituted with 0-3 R^(e), and C₃₋₆ cycloalkylsubstituted with 0-3 R^(e); provided when R² is C₁₋₅ alkyl, the carbonatom except the one attached to the pyridine ring may be replaced by O,N, and S; R³ is independently selected from H, F, Cl, Br, C₁₋₅ alkylsubstituted with 0-3 R^(e), C₂₋₅ alkenyl substituted with 0-3 R^(e),—(CH₂)_(n)OR^(b), —(CH₂)_(n)NR^(a)R^(a), —(CH₂)_(n)CN,—(CH₂)_(n)C(═O)R^(b), —(CH₂)_(n)C(═O)OR^(b), —(CH₂)_(n)C(═O)NR^(a)R^(a),—(CH₂)_(n)NHC(═O)R^(b), —(CH₂)_(n)NHC(═O)NR^(a)R^(a),—(CH₂)_(n)NHC(═O)OR^(b), —(CH₂)_(n)NHS(O)_(p)NR^(a)R^(a),—(CH₂)_(n)NHS(O)_(p)R^(c)—(CH₂)_(n)S(O)_(p)R_(c),—(CH₂)_(n)S(O)_(p)NR^(a)R^(a), —(CH₂)_(n)OC(═O)NR^(a)R^(a); R^(3a) isindependently selected from H, C₁₋₅ alkyl substituted with 0-3 R^(e),—S(O)_(p)R_(c), —C(═O)R^(b), —C(═O)NR^(a)R^(a), —C(═O)OR^(b),—S(O)_(p)NR^(a)R^(a), R⁶, —S(O)_(p)R⁶, —C(═O)R⁶, —C(═O)NR^(a)R⁶,—C(═O)OR⁶, and —S(O)_(p)NR^(a)R⁶; R⁴ is independently selected from H,C₁₋₅ alkyl substituted with 0-3 R^(e), C₂₋₅ alkenyl substituted with 0-3R^(e), —(CH₂)_(n)—C₃₋₆ carbocyclyl substituted with 0-3 R^(e), and—(CH₂)_(n)-heterocyclyl substituted with 0-3 R^(e); R⁵ is independentlyselected from H, R⁶, —OR⁶, —S(O)_(p)R⁶, —C(═O)R⁶, —C(═O)OR⁶, —NR^(a)R⁶,—C(═O)NR^(a)R⁶, —NR^(a)C(═O)R⁶, —NR^(a)C(═O)OR⁶, —OC(═O)NR^(a)R⁶,—S(O)_(p)NR^(a)R⁶, —NR^(a)S(O)_(p)NR^(a)R⁶, and —NR^(a)S(O)_(p)R⁶; R⁶ isindependently selected from —(CR⁷R⁷)_(n)-aryl, —(CR⁷R⁷)_(n)—C₃₋₆cycloalkyl, and —(CR⁷R⁷)_(n)-heteroaryl, each substituted with 1-6 R⁸;R⁷ is independently selected from H, C₁₋₄ alkyl, and —(CH₂)_(n)—C₃₋₁₂carbocyclyl substituted with 0-3 R^(e); R⁸ is independently selectedfrom H, F, Cl, Br, —(CH₂)_(n)CN, —(CH₂)_(n)OR^(b), —(CH₂)_(n)C(═O)R^(b),—(CH₂)_(n)C(═O)OR^(b), —(CH₂)_(n)C(═O)NR^(a)R^(a),—(CH₂)_(n)NR^(a)R^(a), —(CH₂)_(n)NR^(a)C(═O)R^(b),—(CH₂)_(n)NR^(a)C(═O)OR^(b), —(CH₂)_(n)NR^(a)C(═O)NR^(a)R^(a),—(CH₂)_(n)OC(═O)NR^(a)R^(a), —(CH₂)_(n)S(O)_(p)R_(c),—(CH₂)_(n)S(O)_(p)NR^(a)R^(a), —(CH₂)_(n)NR^(a)S(O)_(p)NR^(a)R^(a),—(CH₂)_(n)NR^(a)S(O)_(p)R^(c), C₁₋₄ alkyl substituted with 0-3 R^(e),—(CH₂)_(n)—C₃₋₆ carbocyclyl substituted with 0-3 R^(e), and—(CH₂)_(n)-heterocyclyl substituted with 0-3 R^(e); R⁹ is independentlyselected from C₃₋₆ cycloalkyl, C₃₋₆ cycloalkenyl, aryl, bicycliccarbocyclyl, 6-membered heteroaryl, bicyclic heterocyclyl, eachsubstituted with 1-6 R¹⁰; alternatively, R⁴ and R⁹ together with thenitrogen atom to which they are both attached form a mono or bicyclicheterocyclic ring substituted with 1-6 R¹⁰; R¹⁰ is independentlyselected from H, F, Cl, Br, NO₂, —(CH₂)_(n)OR^(b),—(CH₂)_(n)S(O)_(p)R_(c), —(CH₂)_(n)C(═O)R^(b), —(CH₂)_(n)NR^(a)R^(a),—(CH₂)_(n)CN, —(CH₂)_(n)C(═O)NR^(a)R^(a), —(CH₂)_(n)NR^(a)C(═O)R^(b),—(CH₂)_(n)NR^(a)C(═O)NR^(a)R^(a), —(CH₂)_(n)NR^(a)C(═O)OR^(b),—(CH₂)_(n)OC(═O)NR^(a)R^(a), —(CH₂)_(n)C(═O)OR^(b),—(CH₂)_(n)S(O)_(p)NR^(a)R^(a), —(CH₂)_(n)NR^(a)S(O)_(p)NR^(a)R^(a),—(CH₂)_(n)NR^(a)S(O)_(p)R^(c), C₁₋₄ alkyl substituted with 0-3 R^(e),—(CH₂)_(n)—C₃₋₆ carbocyclyl substituted with 0-3 R^(e), and—(CH₂)_(n)-heterocyclyl substituted with 0-3 R^(e); R^(a) isindependently selected from H, C₁₋₆ alkyl substituted with 0-5 R^(e),C₂₋₆ alkenyl substituted with 0-5 R^(e), C₂₋₆ alkynyl substituted with0-5 R^(e), —(CH₂)_(n)—C₃₋₁₀carbocyclyl substituted with 0-5 R^(e), and—(CH₂)_(n)-heterocyclyl substituted with 0-5 R^(e); or R^(a) and R^(a)together with the nitrogen atom to which they are both attached form aheterocyclic ring substituted with 0-5 R^(e); R^(b) is independentlyselected from H, C₁₋₆ alkyl substituted with 0-5 R^(e), C₂₋₆ alkenylsubstituted with 0-5 R^(e), C₂₋₆ alkynyl substituted with 0-5 R^(e),—(CH₂)_(n)—C₃₋₁₀carbocyclyl substituted with 0-5 R^(e), and—(CH₂)_(n)-heterocyclyl substituted with 0-5 R^(e); R^(c) isindependently selected from C₁₋₆ alkyl substituted with 0-5 R^(e),C₂₋₆alkenyl substituted with 0-5 R^(e), C₂₋₆alkynyl substituted with 0-5R^(e), C₃₋₆carbocyclyl, and heterocyclyl; R^(d) is independentlyselected from H and C₁₋₄alkyl substituted with 0-5 R^(e); R^(e) isindependently selected from C₁₋₆ alkyl substituted with 0-5 R^(f), C₂₋₆alkenyl, C₂₋₆ alkynyl, —(CH₂)_(n)—C₃₋₆ cycloalkyl, —(CH₂)_(n)—C₄₋₆heterocyclyl, —(CH₂)_(n)-aryl, —(CH₂)_(n)-heteroaryl, F, Cl, Br, CN,NO₂, ═O, CO₂H, —(CH₂)_(n)OR^(f), S(O)_(p)R^(f), C(═O)NR^(f)R^(f),NR^(f)C(═O)R^(f), S(O)_(p)NR^(f)R^(f), NR^(f)S(O)_(p)R^(f),NR^(f)C(═O)OR^(f), OC(═O)NR^(f)R^(f) and —(CH₂)_(n)NR^(f)R^(f); R^(f) isindependently selected from H, F, Cl, Br, CN, OH, C₁₋₅alkyl (optimallysubstituted with F, Cl, Br and OH), C₃₋₆ cycloalkyl, and phenyl, orR^(f) and R^(f) together with the nitrogen atom to which they are bothattached form a heterocyclic ring optionally substituted with C₁₋₄alkyl;n is independently selected from zero, 1, 2, 3, and 4; and p isindependently selected from zero, 1, and
 2. 2. The compound of claim 1,having Formula (II):

or a stereoisomer, an enantiomer, a diastereomer, a tautomer, or apharmaceutically acceptable salt thereof, wherein Ring B isindependently selected from

R² is independently selected from C₁₋₅ alkyl substituted with 0-3 R^(e);C₂₋₅ alkenyl, aryl substituted with 0-3 R^(e), heterocyclyl substitutedwith 0-3 R^(e), and C₃₋₆ cycloalkyl; provided when R² is C₁₋₅ alkyl, thecarbon atom except the one attached to the pyridine ring may be replacedby O, N, and S; R³ is independently selected from H, F, Cl, Br, C₁₋₅alkyl substituted with 0-3 R^(e), C₂₋₄ alkenyl; —OR^(b), —NR^(a)R^(a),—CN, —C(═O)R^(b), —C(═O)OR^(b), —C(═O)NR^(a)R^(a), —NHC(═O)R^(b),—NHC(═O)NR^(a)R^(a), —NHC(═O)OR^(b), —NHS(O)_(p)R^(c)—S(O)_(p)R_(c),—S(O)_(p)NR^(a)R^(a), —OC(═O)NR^(a)R^(a); R^(3a) is independentlyselected from H, C₁₋₅ alkyl substituted with 0-3 R^(e), —C(═O)R^(b),—C(═O)NR^(a)R^(a), —C(═O)OR^(b), R⁶, —S(O)_(p)R⁶, —C(═O)R⁶,—C(═O)NR^(a)R⁶, —C(↑O)OR⁶, and —S(O)_(p)NR^(a)R⁶; R⁴ is independentlyselected from H and C₁₋₅ alkyl substituted with 0-3 R^(e); R⁵ isindependently selected from H, R⁶, —OR⁶, —S(O)_(p)R⁶, —C(═O)R⁶,—C(═O)OR⁶, —NR^(a)R⁶, —C(═O)NR^(a)R⁶, —NR^(a)C(═O)R⁶, —NR^(a)C(═O)OR⁶,—OC(═O)NR^(a)R⁶, —S(O)_(p)NR^(a)R⁶, —NR^(a)S(O)_(p)NR^(a)R⁶, and—NR^(a)S(O)_(p)R⁶; R⁶ is independently selected from —(CR⁷R⁷)_(n)-aryl,—(CR⁷R⁷)_(n)—C₃₋₆ cycloalkyl, and —(CR⁷R⁷)_(n)-heteroaryl, eachsubstituted with 1-4 R⁸; R⁷ is independently selected from H and C₁₋₄alkyl; R⁸ is independently selected from H, F, Cl, Br, —(CH₂)_(n)OR^(b),—(CH₂)_(n)C(═O)R^(b), —(CH₂)_(n)C(═O)OR^(b), —(CH₂)_(n)NR^(a)R^(a), CN,—(CH₂)_(n)C(═O)NR^(a)R^(a), —NHC(═O)OR^(b), C₁₋₄ alkyl substituted with0-3 R^(e), (CH₂)_(n)—C₃₋₆ carbocyclyl substituted with 0-3 R^(e), and—(CH₂)_(n)-heterocyclyl substituted with 0-3 R^(e); R⁹ is independentlyselected from C₃₋₆ cycloalkyl, C₃₋₆ cycloalkenyl, and aryl, eachsubstituted with 1-6 R¹⁰; alternatively, R⁴ and R⁹ together with thenitrogen atom to which they are both attached form a heterocyclic ringselected from

R¹⁰ is independently selected from H, F, Cl, Br, —OR^(b), CN, C₁₋₄ alkylsubstituted with 0-3 R^(e) and C₃₋₆ cycloalkyl substituted with 0-3R^(e); R^(a) is independently selected from H, C₁₋₆ alkyl substitutedwith 0-5 R^(e), —(CH₂)_(n)—C₃₋₁₀carbocyclyl substituted with 0-5 R^(e),and —(CH₂)_(n)-heterocyclyl substituted with 0-5 R^(e); or R^(a) andR^(a) together with the nitrogen atom to which they are both attachedform a heterocyclic ring substituted with 0-5 R^(e); R^(b) isindependently selected from H, C₁₋₆ alkyl substituted with 0-5 R^(e),C₂₋₆ alkenyl substituted with 0-5 R^(e), C₂₋₆ alkynyl substituted with0-5 R^(e), —(CH₂)_(n)—C₃₋₁₀carbocyclyl substituted with 0-5 R^(e), and—(CH₂)_(n)-heterocyclyl substituted with 0-5 R^(e); R^(e) isindependently selected from C₁₋₆ alkyl substituted with 0-5 R^(f), C₂₋₆alkenyl, C₂₋₆ alkynyl, —(CH₂)_(n)—C₃₋₆ cycloalkyl, —(CH₂)_(n)—C₄₋₆heterocyclyl, —(CH₂)_(n)-aryl, —(CH₂)_(n)-heteroaryl, F, Cl, Br, CN,NO₂, ═O, CO₂H, —(CH₂)_(n)OR^(f), S(O)_(p)R^(f), C(═O)NR^(f)R^(f),NR^(f)C(═O)R^(f), S(O)_(p)NR^(f)R^(f), NR^(f)S(O)_(p)R^(f),NR^(f)C(═O)OR^(f), OC(═O)NR^(f)R^(f) and —(CH₂)_(n)NR^(f)R^(f); R^(f) isindependently selected from H, F, Cl, Br, CN, OH, C₁₋₅alkyl (optimallysubstituted with F, Cl, Br and OH), C₃₋₆ cycloalkyl, and phenyl; n isindependently selected from zero, 1, 2, and 3; and p is independentlyselected from zero, 1, and
 2. 3. The compound of claim 2, having Formula(III):

or a stereoisomer, an enantiomer, a diastereomer, a tautomer, or apharmaceutically acceptable salt thereof, wherein R² is independentlyselected from C₁₋₅ alkyl substituted with 0-3 R^(e); C₂₋₅ alkenyl, arylsubstituted with 0-3 R^(e), 5-6 membered heterocyclyl substituted with0-3 R^(e), C₃₋₆ cycloalkyl, —(CH₂)₁₋₄OC₁₋₅alkyl, and—(CH₂)₁₋₃OC₃₋₆cycloalkyl; R³ is independently selected from H, F, Cl,and Br; R⁴ is independently selected from H and C₁₋₅ alkyl substitutedwith 0-3 R^(e); R⁵ is independently selected from H, R⁶, —C(═O)R⁶,—NR^(a)R⁶, —C(═O)NR^(a)R⁶, and —NHC(═O)R⁶; R⁶ is independently selectedfrom carbocyclyl selected from

and heterocyclyl selected from

R⁸ is independently selected from H, F, Cl, Br, —(CH₂)_(n)OR^(b),—C(═O)R^(b), —C(═O)OR^(b), —NR^(a)R^(a), CN, —C(═O)NR^(a)R^(a),—NHC(═O)OR^(b), C₁₋₄ alkyl substituted with 0-3 R^(e), —(CH₂)_(n)—C₃₋₆carbocyclyl substituted with 0-3 R^(e), and —(CH₂)_(n)-heterocyclylsubstituted with 0-3 R^(e); R⁹ is independently selected from

alternatively, R⁴ and R⁹ together with the nitrogen atom to which theyare both attached form a heterocyclic ring selected from

R¹⁰ is independently selected from H, F, Cl, CN, C₁₋₄ alkyl, and OC₁₋₄alkyl; R^(a) is independently selected from H, C₁₋₆ alkyl substitutedwith 0-5 R^(e), —(CH₂)_(n)—C₃₋₁₀carbocyclyl substituted with 0-5 R^(e),and —(CH₂)_(n)-heterocyclyl substituted with 0-5 R^(e); or R^(a) andR^(a) together with the nitrogen atom to which they are both attachedform a heterocyclic ring substituted with 0-5 R^(e); R^(b) isindependently selected from H, C₁₋₆ alkyl substituted with 0-5 R^(e),C₂₋₆ alkenyl substituted with 0-5 R^(e), C₂₋₆ alkynyl substituted with0-5 R^(e), —(CH₂)_(n)—C₃₋₁₀carbocyclyl substituted with 0-5 R^(e), and—(CH₂)_(n)-heterocyclyl substituted with 0-5 R^(e); R^(e) isindependently selected from C₁₋₆ alkyl substituted with 0-5 R^(f), C₂₋₆alkenyl, C₂₋₆ alkynyl, —(CH₂)_(n)—C₃₋₆ cycloalkyl, —(CH₂)_(n)—C₄₋₆heterocyclyl, —(CH₂)_(n)-aryl, —(CH₂)_(n)-heteroaryl, F, Cl, Br, CN,NO₂, ═O, CO₂H, —(CH₂)_(n)OR^(f), S(O)_(p)R^(f), C(═O)NR^(f)R^(f),NR^(f)C(═O)R^(f), S(O)_(p)NR^(f)R^(f), NR^(f)S(O)_(p)R^(f),NR^(f)C(═O)OR^(f), OC(═O)NR^(f)R^(f) and —(CH₂)_(n)NR^(f)R^(f); R^(f) isindependently selected from H, F, Cl, Br, CN, OH, C₁₋₅alkyl (optimallysubstituted with F, Cl, Br and OH), C₃₋₆ cycloalkyl, and phenyl; n isindependently selected from zero, 1, 2, and 3; and p is independentlyselected from zero, 1, and
 2. 4. The compound of claim 3, having formula(IV):

or a stereoisomer, an enantiomer, a diastereomer, a tautomer, or apharmaceutically acceptable salt thereof, wherein R² is independentlyselected from —CH₂CH₂CH₃, —CH₂CH₂CH₂CH₃, —CH₂CH₂CH(CH₃)₂,

—CH₂OCH₃, —CH₂OCH₂CH₃, and —CH₂OCH(CH₃)₂; R³ is independently selectedfrom H, F, Cl, and Br; R⁴ is independently selected from —CH₃, —CH₂CH₃,—CH₂CH₂CH₃, and —CH₂(CH₃)₂; R⁵ is R⁶; R⁶ is independently selected from

R⁸ is independently selected from H, F, Cl, Br, —(CH₂)₀₋₁OC₁₋₄ alkyl,C₁₋₄ alkyl and —C(═O)N(C₁₋₄alkyl)₂; and R¹⁰ is independently selectedfrom H, F, Cl, CN, —CH₃, —CH₂CH₃, and —OMe.
 5. The compound of claim 3,having formula (V):

or a stereoisomer, an enantiomer, a diastereomer, a tautomer, or apharmaceutically acceptable salt thereof, wherein R² is independentlyselected from —CH₂CH₂CH₃, —CH₂CH₂CH₂CH₃, —CH₂CH₂CH(CH₃)₂,

—CH₂OCH₃, —CH₂OCH₂CH₃, and —CH₂OCH(CH₃)₂; R³ is independently selectedfrom H, F, Cl, and Br; R⁴ and R⁹ together with the nitrogen atom towhich they are both attached form a heterocyclic ring selected from

R⁵ is R⁶; R⁶ is independently selected from

R⁸ is independently selected from H, F, Cl, Br, —(CH₂)₀₋₁OC₁₋₄ alkyl,C₁₋₄ alkyl and —C(═O)N(C₁₋₄alkyl)₂; and R¹⁰ is independently selectedfrom H, F, Cl, CN, —CH₃, —CH₂CH₃, and —OCH₃.
 6. The compound of claim 2,having Formula (VI):

or a stereoisomer, an enantiomer, a diastereomer, a tautomer, or apharmaceutically acceptable salt thereof, wherein Ring A isindependently selected from

R² is independently selected from C₁₋₅ alkyl substituted with 0-3 R^(e);C₂₋₅ alkenyl, aryl substituted with 0-3 R^(e), heterocyclyl substitutedwith 0-3 R^(e), and C₃₋₆ cycloalkyl; provided when R² is C₁₋₅ alkyl, thecarbon atom except the one attached to the pyridine ring may be replacedby O, N, and S; R^(3a) is independently selected from H, C₁₋₅ alkylsubstituted with 0-3 R^(e), —C(═O)R^(b), —C(═O)NR^(a)R^(a),—C(═O)OR^(b), R⁶, —S(O)_(p)R⁶, —C(═O)R⁶, —C(═O)NR^(a)R⁶, —C(═O)OR⁶, and—S(O)_(p)NR^(a)R⁶; R⁴ is independently selected from H and C₁₋₅ alkylsubstituted with 0-3 R^(e); R⁵ is independently selected from H, R⁶,—OR⁶, —S(O)_(p)R⁶, —C(═O)R⁶, —C(═O)OR⁶, —NR^(a)R⁶, —C(═O)NR^(a)R⁶,—NR^(a)C(═O)R⁶, —NR^(a)C(═O)OR⁶, —OC(═O)NR^(a)R⁶, —S(O)_(p)NR^(a)R⁶,—NR^(a)S(O)_(p)NR^(a)R⁶, and —NR^(a)S(O)_(p)R⁶; R⁶ is independentlyselected from —(CR⁷R⁷)_(n)-aryl, —(CR⁷R⁷)_(n)—C₃₋₆ cycloalkyl, and—(CR⁷R⁷)_(n)-heteroaryl, each substituted with 1-4 R⁸; R⁷ isindependently selected from H and C₁₋₄ alkyl; R⁸ is independentlyselected from H, F, Cl, Br, —OR^(b), —(CH₂)_(n)C(═O)R^(b),—(CH₂)_(n)C(═O)OR^(b), —(CH₂)_(n)NR^(a)R^(a), CN,—(CH₂)_(n)C(═O)NR^(a)R^(a), —NHC(═O)OR^(b), C₁₋₄ alkyl substituted with0-3 R^(e), —(CH₂)_(n)—C₃₋₆ carbocyclyl substituted with 0-3 R^(e), and—(CH₂)_(n)-heterocyclyl substituted with 0-3 R^(e); R⁹ is independentlyselected from C₃₋₆ cycloalkyl, C₃₋₆ cycloalkenyl, and aryl, eachsubstituted with 1-3 R¹⁰; alternatively, R⁴ and R⁹ together with thenitrogen atom to which they are both attached form a heterocyclic ringselected from

R¹⁰ is independently selected from H, F, Cl, Br , —OR^(b), CN, C₁₋₄alkyl substituted with 0-3 R^(e) and C₃₋₆ cycloalkyl substituted with0-3 R^(e); R^(a) is independently selected from H, C₁₋₆ alkylsubstituted with 0-5 R^(e), —(CH₂)_(n)—C₃₋₁₀carbocyclyl substituted with0-5 R^(e), and —(CH₂)_(n)-heterocyclyl substituted with 0-5 R^(e); orR^(a) and R^(a) together with the nitrogen atom to which they are bothattached form a heterocyclic ring substituted with 0-5 R^(e); R^(b) isindependently selected from H, C₁₋₆ alkyl substituted with 0-5 R^(e),C₂₋₆ alkenyl substituted with 0-5 R^(e), C₂₋₆ alkynyl substituted with0-5 R^(e), —(CH₂)_(n)—C₃₋₁₀carbocyclyl substituted with 0-5 R^(e), and—(CH₂)_(n)-heterocyclyl substituted with 0-5 R^(e); R^(e) isindependently selected from C₁₋₆ alkyl substituted with 0-5 R^(f), C₂₋₆alkenyl, C₂₋₆ alkynyl, —(CH₂)_(n)—C₃₋₆ cycloalkyl, —(CH₂)_(n)—C₄₋₆heterocyclyl, —(CH₂)_(n)-aryl, —(CH₂)_(n)-heteroaryl, F, Cl, Br, CN,NO₂, ═O, CO₂H, —(CH₂)_(n)OR^(f), S(O)_(p)R^(f), C(═O)NR^(f)R^(f),NR^(f)C(═O)R^(f), S(O)_(p)NR^(f)R^(f), NR^(f)S(O)_(p)R^(f),NR^(f)C(═O)OR^(f), OC(═O)NR^(f)R^(f) and —(CH₂)_(n)NR^(f)R^(f); R^(f) isindependently selected from H, F, Cl, Br, CN, OH, C₁₋₅alkyl (optimallysubstituted with F, Cl, Br and OH), C₃₋₆ cycloalkyl, and phenyl; n isindependently selected from zero, 1, 2, and 3; and p is independentlyselected from zero, 1, and
 2. 7. The compound according to claim 6, or astereoisomer, an enantiomer, a diastereomer, a tautomer, or apharmaceutically acceptable salt thereof, wherein Ring A isindependently selected from

R² is independently selected from C₁₋₅ alkyl substituted with 0-3 R^(e);C₂₋₅ alkenyl, aryl substituted with 0-3 R^(e), 5-6 membered heterocyclylsubstituted with 0-3 R^(e), C₃₋₆ cycloalkyl, —(CH₂)₁₋₄OC₁₋₅alkyl, and—(CH₂)₁₋₃OC₃₋₆cycloalkyl; R^(3a) is independently selected from H andC₁₋₅ alkyl substituted with 0-3 R^(e); R⁴ is independently selected fromH and C₁₋₅ alkyl substituted with 0-3 R^(e); R⁵ is independentlyselected H and R⁶; R⁶ is independently selected from carbocyclylselected from

and heterocyclyl selected from

R⁸ is independently selected from H, F, Cl, Br, —OR^(b), —C(═O)R^(b),—C(═O)OR^(b), —NR^(a)R^(a), CN, —C(═O)NR^(a)R^(a), —NHC(═O)OR^(b), C₁₋₄alkyl substituted with 0-3 R^(e), —(CH₂)_(n)—C₃₋₆ carbocyclylsubstituted with 0-3 R^(e), and —(CH₂)_(n)-heterocyclyl substituted with0-3 R^(e); R⁹ is independently selected from

alternatively, R⁴ and R⁹ together with the nitrogen atom to which theyare both attached form a heterocyclic ring selected from

R¹⁰ is independently selected from H, F, Cl, CN, C₁₋₄ alkyl, and OC₁₋₄alkyl; R^(a) is independently selected from H, C₁₋₆ alkyl substitutedwith 0-5 R^(e), —(CH₂)_(n)—C₃₋₁₀carbocyclyl substituted with 0-5 R^(e),and —(CH₂)_(n)-heterocyclyl substituted with 0-5 R^(e); or R^(a) andR^(a) together with the nitrogen atom to which they are both attachedform a heterocyclic ring substituted with 0-5 R^(e); R^(b) isindependently selected from H, C₁₋₆ alkyl substituted with 0-5 R^(e),C₂₋₆ alkenyl substituted with 0-5 R^(e), C₂₋₆ alkynyl substituted with0-5 R^(e), —(CH₂)_(n)—C₃₋₁₀carbocyclyl substituted with 0-5 R^(e), and—(CH₂)_(n)-heterocyclyl substituted with 0-5 R^(e); R^(e) isindependently selected from C₁₋₆ alkyl substituted with 0-5 R^(f), C₂₋₆alkenyl, C₂₋₆ alkynyl, —(CH₂)_(n)—C₃₋₆ cycloalkyl, —(CH₂)_(n)—C₄₋₆heterocyclyl, —(CH₂)_(n)-aryl, —(CH₂)_(n)-heteroaryl, F, Cl, Br, CN,NO₂, ═O, CO₂H, —(CH₂)_(n)OR^(f), S(O)_(p)R^(f), C(═O)NR^(f)R^(f),NR^(f)C(═O)R^(f), S(O)_(p)NR^(f)R^(f), NR^(f)S(O)_(p)R^(f),NR^(f)C(═O)OR^(f), OC(═O)NR^(f)R^(f) and —(CH₂)_(n)NR^(f)R^(f); R^(f) isindependently selected from H, F, Cl, Br, CN, OH, C₁₋₅alkyl (optimallysubstituted with F, Cl, Br and OH), C₃₋₆ cycloalkyl, and phenyl; n isindependently selected from zero, 1, 2, and 3; and p is independentlyselected from zero, 1, and
 2. 8. The compound according to claim 7,having Formula (VII):

or a stereoisomer, an enantiomer, a diastereomer, a tautomer, or apharmaceutically acceptable salt thereof, wherein R² is independentlyselected from C₁₋₅ alkyl substituted with 0-3 R^(e); C₂₋₅ alkenyl, arylsubstituted with 0-3 R^(e), 5-6 membered heterocyclyl substituted with0-3 R^(e), C₃₋₆ cycloalkyl, —(CH₂)₁₋₄OC₁₋₅alkyl, and—(CH₂)₁₋₃OC₃₋₆cycloalkyl; R⁴ is independently selected from H and C₁₋₄alkyl; R⁵ is independently selected from H and R⁶; R⁶ is independentlyselected from

R⁸ is independently selected from H, F, Cl, Br, —(CH₂)₀₋₁OC₁₋₄ alkyl,C₁₋₄ alkyl, and —C(═O)N(C₁₋₄alkyl)₂; R⁹ is independently selected from

alternatively, R⁴ and R⁹ together with the nitrogen atom to which theyare both attached form a heterocyclic ring selected from

R¹⁰ is independently selected from H, F, Cl, CN, C₁₋₄ alkyl, and OC₁₋₄alkyl; R^(a) is independently selected from H, C₁₋₆ alkyl substitutedwith 0-5 R^(e), —(CH₂)_(n)—C₃₋₁₀carbocyclyl substituted with 0-5 R^(e),and —(CH₂)_(n)-heterocyclyl substituted with 0-5 R^(e); or R^(a) andR^(a) together with the nitrogen atom to which they are both attachedform a heterocyclic ring substituted with 0-5 R^(e); R^(b) isindependently selected from H, C₁₋₆ alkyl substituted with 0-5 R^(e),C₃₋₁₀carbocyclyl, and heterocyclyl substituted with 0-5 R^(e); R^(e) isindependently selected from C₁₋₆ alkyl (optionally substituted with Fand Cl), OH, OCH₃, OCF₃, —(CH₂)_(n)—C₃₋₆ cycloalkyl, —(CH₂)_(n)—C₄₋₆heterocyclyl, —(CH₂)_(n)-aryl, —(CH₂)_(n)-heteroaryl, F, Cl, Br, CN,NO₂, ═O, and CO₂H; and n is independently selected from zero, 1, 2, and3.
 9. The compound according to claim 8, or a stereoisomer, anenantiomer, a diastereomer, a tautomer, or a pharmaceutically acceptablesalt thereof, wherein R² is independently selected from —CH₂CH₂CH₃,—CH₂CH₂CH₂CH₃, —CH₂CH₂CH(CH₃)₂,

—CH₂OCH₃, —CH₂OCH₂CH₃, and —CH₂OCH(CH₃)₂; R⁴ is independently selectedfrom —CH₃, —CH₂CH₃, —CH₂CH₂CH₃, and —CH₂(CH₃)₂; R⁵ is R⁶; R⁶ isindependently selected from

R⁸ is independently selected from H, F, Cl, and Br; R⁹ is

alternatively, R⁴ and R⁹ together with the nitrogen atom to which theyare both attached form a heterocyclic ring selected from

and R¹⁰ is independently selected from H, F, Cl, CN, C₁₋₄ alkyl, andOC₁₋₄ alkyl.
 10. The compound according to claim 9, or a stereoisomer,an enantiomer, a diastereomer, a tautomer, or a pharmaceuticallyacceptable salt thereof, wherein R⁹ is

and R¹⁰ is independently selected from H, F, Cl, CN, C₁₋₄ alkyl, andOC₁₋₄ alkyl.
 11. The compound according to claim 9, or a stereoisomer,an enantiomer, a diastereomer, a tautomer, or a pharmaceuticallyacceptable salt thereof, wherein R⁴ and R⁹ together with the nitrogenatom to which they are both attached form a heterocyclic ring selectedfrom

and R¹⁰ is independently selected from H, F, Cl, CN, C₁₋₄ alkyl, andOC₁₋₄ alkyl.
 12. A compound according to claim 1, wherein the compoundis selected from the exemplified examples or a stereoisomer, a tautomer,or a pharmaceutically acceptable salt thereof.
 13. A pharmaceuticalcomposition, comprising a pharmaceutically acceptable carrier and acompound of to claim 1, or a stereoisomer, a tautomer, or apharmaceutically acceptable salt thereof.
 14. A method of treatingcardiovascular diseases, comprising administering to a patient in needthere of a therapeutically effective amount of the pharmaceuticalcomposition of claim
 13. 15. The method of claim 14 wherein saidcardiovascular diseases are coronary heart disease, stroke, heartfailure, systolic heart failure, diastolic heart failure, diabetic heartfailure, heart failure with preserved ejection fraction, cardiomyopathy,myocardial infarction, left ventricular dysfunction, left ventriculardysfunction after myocardial infarction, cardiac hypertrophy, myocardialremodeling, myocardial remodeling after infarction or after cardiacsurgery and valvular heart diseases.